Thienopyrimidine-based agents bearing diphenylurea: Design, synthesis, and evaluation of antiproliferative and antiangiogenic activity.

An important role has been considered for the vascular endothelial growth factor receptor 2 (VEGFR-2) in the angiogenesis process, so that its inhibition is an important scientific way for cancer treatment. In this work, new thienopyrimidine derivatives were synthesized and evaluated. Compared with sorafenib, the majority of the target compounds had antiproliferative activity against the PC3, HepG2, MCF7, SW480, and HUVEC cell lines, especially 9h with IC50 values of 4.5-15.1 µM, confirming the noticeable cytotoxic effects on the listed cell lines (PC3, HepG2, SW480, and HUVEC). Analyses by flow cytometry on SW480 and HUVEC cells revealed that 9n, 9k, 9h, and 9q led to apoptotic cell death. The result of the chick chorioallantoic membrane assay showed that 9h effectively reduced the number of corresponding blood vessels. Finally, the inhibitory effect on VEGFR-2 phosphorylation was considered as the outcome of Western blot analysis of compound 9h.

Meta-analysis of the anti-oxidative and anti-inflammatory effects of hypoglycaemic plant-derived medicines.

BACKGROUND: The pivotal role of oxidative stress and inflammation in the pathophysiology of type 2 diabetes mellitus (T2DM) has been firmly established. However, the evidence concerning hypoglycaemic medicinal plants' antioxidant and anti-inflammatory effects remains inconclusive due to inconsistencies in prior studies. To address this gap, our study aims to perform a comprehensive systematic review and meta-analysis of randomized controlled trials (RCTs) to consolidate previous research findings in this field. METHODS: We conducted a comprehensive search in the PubMed, Web of Science, Embase, Cochrane Library, and Scopus databases to identify relevant English randomized controlled trials (RCTs). Our study adhered to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. All eligible studies that evaluated concurrently the antioxidative and anti-inflammatory effects of hypoglycaemic plant-derived supplements on type 2 diabetes mellitus (T2DM) were included in the meta-analysis. The meta-analysis itself was carried out using both fixed and random effects models to synthesize the findings from the selected studies. RESULTS: Our study included 47 trials with a total of 2636 participants, both male and female, aged between 20 and 79 years, diagnosed with prediabetes, type 2 diabetes mellitus (T2DM), or metabolic syndrome. The meta-analysis revealed that plant-derived treatments, compared to placebos or other medicines, significantly improved oxidative stress (SMD = - 0.36, 95% CI - 0.64 to - 0.09), inflammation (SMD = - 0.47, 95% CI - 0.63 to - 0.31), total antioxidant capacity (SMD = 0.46, 95% CI 0.16-0.75), and antioxidant enzyme activity (SMD = 1.80, 95% CI 1.26-2.33). The meta-regression analysis showed that treatment duration exceeding 8 weeks significantly impacted the heterogeneity of the oxidative stress data. CONCLUSIONS: Several hypoglycaemic plant-based treatments appear to positively affect T2DM patients by concurrently lowering oxidative stress and inflammatory indicators and boosting antioxidant enzyme activity. CLINICAL TRAIL REGISTRY: PROSPERO ID: CRD42021226147.

Circular RNA; a new biomarker for breast cancer: A systematic review.

Circular RNAs (circRNAs) were recently discovered as a looped subset of competing endogenous RNAs, with an ability to regulate gene expression by microRNA sponging. There are several studies on their potential roles in cancer development, such as colorectal cancer and basal cell carcinoma. However, there is still a significant gap in the knowledge about circRNA functions in breast cancer (BC) progression. The current study systematically reviewed circRNA biogenesis and their potential roles as a novel biomarker in BC on published studies of the MEDLINE®/PubMed, Cochrane®, and Scopus® databases. The obtained results showed a general dysregulation of circRNAs expression in BC cells with a cell-type and stage-specific manner. The potential connection between circRNAs and BC cell proliferation, apoptosis, metastasis, and chemotherapy sensitivity and resistance were discussed.

Ultrasound features of pregnancy-associated breast cancer: A retrospective observational analysis.

Pregnancy-associated breast cancer (PABC) is a poor prognosis in women, and the mortality rate is higher in this subgroup of patients than in non-PABC. This study aims to assess clinicopathological and ultrasound features of patients with PABC. Of 75 patients with breast cancer, 31 cases were in lactating, or pregnancy phase and 44 patients had no recent history of pregnancy/lactation at the time of cancer detection. The available pathological characteristics and ultrasound findings of the PABC and non-PABC groups were compared. The analysis of ultrasound findings demonstrated that the percentages of antiparallel orientation (p = 0.04) and heterogeneous internal echo pattern (p = 0.002) were higher in the PABC group. The final Breast Imaging Reporting and Data System (BI-RADS) assessment in the two groups was significantly different (p = 0.008). In this study, most PABCs were BI-RADS 4c or 5; compared with age-matched non-PABC cases. There were significant differences in ER (p = 0.03), receptor groups (p = 0.007), and tumor grade (p = 0.02) in PABC compared to non-PABC group. To conclude, radiologists should be careful about ultrasound findings of PABC and recommend core needle biopsy in suspected cases.

Antioxidative hypoglycemic herbal medicines with in vivo and in vitro activity against C-reactive protein; a systematic review.

BACKGROUND: Inflammation is a double-edged sword in the pathophysiology of chronic diseases, such as type 2 diabetes mellitus (T2DM). The global rise in the prevalence of T2DM in one hand, and poor disease control with currently-available treatments on the other hand, along with an increased tendency towards the use of natural products make scientists seek herbal medicines for the management of diabetes and its complications by reducing C-reactive protein (CRP) as an inflammatory marker. PURPOSE: To systematically review the literature to identify the efficacy of various medicinal plants with antioxidative and anti-inflammatory properties considering their effect on CRP in animal models of T2DM. STUDY DESIGN: systematic review. METHODS: Electronic databases including PubMed, Scopus, Web of Science and Cochran Library were searched using the search terms "herbal medicine", "diabetes", "c-reactive protein", "antioxidants" till August 2021. The quality of evidence was assessed using the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE's) tool. The study protocol was registered in PROSPERO with an ID number CRD42020207190. A manual search to detect any articles not found in the databases was also made. The identified studies were then critically reviewed and relevant data were extracted and summarized. RESULTS: Among total of 9904 primarily-retrieved articles, twenty-three experimental studies were finally included. Our data indicated that numerous herbal medicines, compared to placebo or hypoglycemic medications, are effective in treatment of diabetes and its complications through decreasing CRP concentrations and oxidative stresses levels. Medicinal plants including Psidium guajava L., Punica granatum L., Ginkgo biloba L., Punica granatum L., Dianthus superbusn L.. Moreover, Eichhornia crassipes (Mart.) Solms, Curcuma longa L., Azadirachta indica A. Juss., Morus alba L., and Ficus racemosa L. demonstrated potential neuroprotective effects in animal models of diabetes. CONCLUSION: Hypoglycemic medicinal plants discussed in this review seem to be promising regulators of CRP, and oxidative stress. Thus, these plants are suitable candidates for management of diabetes' complications. Nevertheless, further high-quality in vivo studies and clinical trials are required to confirm these effects.

A coumarin-based fluorescent chemosensor as a Sn indicator and a fluorescent cellular imaging agent.

In the present study, fluorogenic coumarin-based probes (1-3) through condensation of 4-hydroxy coumarin with malondialdehyde bis(diethyl acetal)/triethyl orthoformate were prepared. The absorption and fluorescence emission properties of 2b and 3 in different solvents were studied, and a considerable solvatochromic effect was observed. The sensitivity of chemosensors 2b and 3 toward various cations and anions was investigated. It was revealed that compound 3 had a distinct selectivity toward Sn2+, possibly via a chelation enhanced quenching mechanism. The fluorescence signal was quenched over the concentration range of 6.6-120 µM, with an LOD value of 3.89 µM. The cytotoxicity evaluation of 3 against breast cancer cell lines demonstrated that the chemosensor was nontoxic and could be used successfully in cellular imaging. The probe responded to tin ions not only via fluorescence quenching, but also through colorimetric signal change. The change in optical properties was observed in ambient conditions and inside living cells.

Vitamin D and breast cancer risk: A systematic review and meta-analysis in Iranian patients.

•BsmI and TaqI have association with breast cancer risk in Iranian women.•No significant associations were identified between the FokI and ApaI and breast cancer risk in Iranian women.•No association was detected between Vitamin D level and breast cancer in Iranian women.

Withdrawal reasons of randomized controlled trials on type 2 diabetes: a systematic review.

PURPOSE: Type 2 diabetes mellitus (T2DM) is the subject of numerous randomized controlled trials (RCTs). The validity of RCTs may be threatened by attrition bias due to the discontinuation of the study. The aim of this systematic review is to evaluate the reasons of patient's withdrawal from these RCTs. METHODS: A systematic literature search on PubMed, Cochrane Library, Web of Science, and Scopus databases was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. The aim was to obtain all relevant blinded RCTs published before January 2017 in which the effectiveness of synthetic drugs, vitamins/minerals were compared to that of placebo or active control in T2DM. The quality of RCTs was assessed using the Jadad score. The frequency of withdrawal reasons was presented based on treatments with placebo/active control, national/international level of the studies, and publication year. Meta-analysis was not performed due to the heterogeneity. RESULTS: Overall, 1368 articles comprising of 640,780 subjects were included. In the majority of the RCTs (75.0%), the intervention and the placebo arms were compared. Most of the included studies (96%) were classified in the high-quality category (Jadad score≥3). The highest proportion of reported withdrawal cases was found in international studies, national RCTs conducted in Japan, and RCTs published in 2011. The withdrawal reasons were reported for 91,669 (63.75%) of the total 143,794 participants who had withdrawn from these studies. The main reported reasons were "adverse effects" (24.04%), "withdraw consent" (16.10%), and "missing data" (11.08%). Variations in the reported withdrawal reasons were based on the country or published year. RCTs with triple blinded design as well as those in which anti-hyperlipidemia and anti-obesity medications were applied, showed significantly higher probability of reported the withdrawal. CONCLUSION: High proportion of reported discontinuation in blinded RCTs on patients with T2DM was related to drug adverse effects. Overall, the total number and reason of drop out were unsatisfactory.

Design, synthesis and evaluation of novel thienopyrimidine-based agents bearing diaryl urea functionality as potential inhibitors of angiogenesis.

Inhibition of angiogenesis is a promising strategy for the treatment of cancer. Herein, we describe the design and synthesis of thieno[2,3-d]pyrimidine-1,3,4-thiadiazole-aryl urea derivatives 11a-m to evaluate their efficacy in the chick chorioallantoic membrane (CAM) assay. Among target agents, 11i had a considerable activity against prostate cancer cell line, PC3 (IC50 = 3.6 µM). Moreover, induction of apoptosis, good inhibitory activity against the growth of capillary blood vessels, and inhibition of VEGFR-2 phosphorylation were noticeable parameters which convinced us that 11i could be considered as a promising candidate for the discovery of novel drugs to treat tumors, particularly prostate cancer.

6-Cinnamoyl-4-arylaminothienopyrimidines as highly potent cytotoxic agents: Design, synthesis and structure-activity relationship studies.

In this paper, we described the synthesis and cytotoxic activities of two new series of thieno[2,3-d]pyrimidine and thieno[3,2-d] pyrimidine derivatives. Most of the synthesized compounds had significant antiproliferative activities against PC3, MDA-MB-231, A549, and HeLa cell lines in comparison to the reference drug, erlotinib. Compounds N-(4-((3,5-dichlorophenyl)amino)thieno[2,3-d]pyrimidin-6-yl)cinnamamide 8e and (E)-N-(4-((3,4-dichlorophenyl)amino)thieno[2,3-d]pyrimidin-6-yl)-3-(4-methoxyphenyl)acrylamide 8g with IC50 values of 4 nM and 33 nM, respectively, against HeLa cell line were chosen for further studies. The apoptosis induced activity and cell cycle arrest were determined and the results provided evidence that these compounds induced cell death via apoptosis and arrested cell growth in sub-G1 phase. In addition, western blot analysis manifested the promising result of suppressing the EGFR signaling pathway (p-EGFR/p-ERK1/2). The docking studies appreciated the considerable potency of compound 8e based on hydrogen and covalent binding interactions. Eventually, in silico pharmacokinetic prediction indicated the acceptable bioavailability of all final compounds.

Evaluation of Poly(I:C) and combination of CpG ODN plus Montanide ISA adjuvants to enhance the efficacy of outer membrane vesicles as an acellular vaccine against Brucella melitensis infection in mice.

Brucellosis is the most common zoonotic disease worldwide and still there is no vaccine for human use. The commercial animal vaccines also have major problems that limit their use. Therefore, there is a need for an effective Brucella vaccine which is multivalent and produces a good protective immunity with minimal disadvantages. Due to their heterogeneous composition and diverse functions, OMVs are promising acellular vaccine candidates against brucellosis. In the present study, the potential of Poly(I:C) or CpG ODN 1826+ Montanide ISA 70 VG adjuvant formulations were evaluated to enhance the immunity and protection levels conferred by OMVs against Brucella challenge in mice. The results indicated that both vaccine regimens were able to induce strong Th1-biased responses and confer protective levels significantly higher than REV.1 live vaccine. With regard to the results, it is concluded that OMVs in either adjuvant can be introduced as a new vaccine candidate against B. melitensis infection.

Chondrosarcoma: An overview of clinical behavior, molecular mechanisms mediated drug resistance and potential therapeutic targets.

Sarcomas are known as a heterogeneous class of cancers arisen in the connective tissues and demonstrated various histological subtypes including both soft tissue and bone origin. Chondrosarcoma is one of the main types of bone sarcoma that shows a considerable deficiency in response to chemotherapy and radiotherapy. While conventional treatment based on surgery, chemo-and radiotherapy are used in this tumor, high rate of death especially among children and adolescents are reported. Due to high resistance to current conventional therapies in chondrosarcoma, there is an urgent requirement to recognize factors causing resistance and discover new strategies for optimal treatment. In the past decade, dysregulation of genes associated with tumor development and therapy resistance has been studied to find potential therapeutic targets to overcome resistance. In this review, clinical aspects of chondrosarcoma are summarized. Moreover, it gives a summary of gene dysregulation, mutation, histone modifications and non-coding RNAs associated with tumor development and therapeutic response modulation. Finally, the probable role of tumor microenvironment in chondrosarcoma drug resistance and targeted therapies as a promising molecular therapeutic approach are summarized.