Development of venetoclax performance using its new derivatives on BCL-2 protein inhibition

Cancer cells are resistant to apoptosis and this is one of the most obvious symptoms of cancer in humans. One of the most exciting strategies for treating cancer is to design regulators that increase cell death and stop cell growth. Members of the BCL-2 family of proteins play an important role in the regulation of apoptosis. In this study, an attempt was made to improve the performance of one of the anticancer drugs by designing new analogs of venetoclax (VNT). For this purpose, molecular docking studies were performed to determine the best binding state of VNT and its newly designed derivatives at the protein-binding site to estimate the binding energy. The best analog in terms of free energy was VNT-12 with the lowest energy (−12.15 kcal/mol). Finally, to investigate the inhibitory effect of the compounds on BCL-2 protein, molecular dynamics simulation was used, and by performing the relevant analyses during the simulation, it was observed that the newly designed ligand had better performance in inhibiting BCL-2 protein compared to VNT.     

Organ-specific or personalized treatment for COVID-19: rationale,evidence, and potential candidates

Functional & Integrative Genomics - Although extrapulmonary manifestations of coronavirus disease 2019 (COVID-19) are increasingly reported, no effective therapeutic strategy for these...     

Circular RNA-associated ceRNA network involved in HIF-1 signalling in triple-negative breast cancer: circ_0047303 as a potential key regulator

The aggressive and highly metastatic nature of triple-negative breast cancer (TNBC) causes patients to suffer from the poor outcome. HIF-1 signalling pathway is a prominent pathway that contributes to angiogenesis and metastasis progression in tumours. On the contrary, the undeniable importance of circular RNAs (circRNAs) as multifunctional non-coding RNAs (ncRNAs) has been identified in breast cancer. These ncRNAs owing to their high stability and specificity have been becoming a hotspot in cancer researches. circRNAs act as competing endogenous RNAs (ceRNAs) and compete with mRNAs for shared miRNAs, thus modulate gene expression. Since the most dysregulated biological functions in TNBC are associated with cellular invasion, understanding the molecular pathogenesis of these processes is a crucial step towards the development of new treatment approaches. The purpose of this study is to undermine the circRNA-associated ceRNA network involved in HIF-1 signalling in TNBC using an integrative bioinformatics approach. In the next step, the novel circ_0047303-mediated ceRNA regulatory axes have been extracted and validated across TNBC samples. We show that circ_0047303 has the highest degree in the circRNA-associated ceRNA network and shows a significant up-expression in TNBC. Moreover, our results suggest that circ_0047303 could mediate the upregulation of key angiogenesis-related genes, including HIF-1, EIF4E2 and VEGFA in TNBC through sponging the tumour-suppressive miRNAs. The circ_0047303 could be a promising molecular biomarker and/or therapeutic target for TNBC.     

Aerobic exercise modulates noncoding RNA network upstream of FNDC5 in the Gastrocnemius muscle of high-fat-diet-induced obese mice

Journal of Physiology and Biochemistry - The purpose of the study was to determine the influence of aerobic exercise with a fat-rich diet on ncRNAs expression associated with FNDC5 in the...     

Evaluation of the efficiency of modified PAMAM dendrimer with low molecular weight protamine peptide to deliver IL-12 plasmid into stem cells as cancer therapy vehicles

Interleukin 12 (IL-12) is considered as an important molecule for cancer immunotherapy with significant roles in hindering tumor activity, mostly mediated by tumor-associated macrophages and anti-angiogenic factors. Mesenchymal stem cells (MSCs) have been come out as promising carriers to increase the accumulation of drug/gene in tumor sites. As a vehicle, MSCs have various advantages, including tumor-specific propensity and migratory ability; however, they have limited transfection efficiency, compared to other cells. In this study, we introduced a novel delivery system based on poly-(amidoamine) (PAMAM) (G5) to deliver a plasmid encoding IL-12 to MSCs. Initially, 30% of the amine surface of PAMAM was substituted by 10-bromodecanoic acid. Then, the low molecular weight of protamine peptide was conjugated to PAMAM and PAMAM-alkyl with N-succinimidyl 3-(2-pyridyldithio) propionate as a linker. Physicochemical properties of this modified PAMAM were evaluated, including size and surface charge, toxicity, transfection efficiency to deliver reporter and IL-12 genes into MSCs and finally the migration potential of the engineered stem cells into cancer and normal cell lines (HepG2 and NIH/3 T3). The results showed that alkyl-peptide modified PAMAM with low toxicity had a higher potential to deliver green fluorescent protein and IL-12 genes to stem cells, than PMAMAM, PAMAM-alkyl and PAMAM-peptide. These engineered stem cells had a greater ability to migrate to cancer cells than normal cells. It can be concluded that engineered stem cells containing the IL-12 gene can be considered as an efficient cell carrier for cancer immunotherapy. Further clinical studies are needed to confirm these results.     

Bacterial infections in the early period after liver transplantation in adults: A prospective single-center cohort study

Liver transplantation (LT) is a potentially curative treatment for terminal stage hepatic diseases. Bacterial infections are the main causes of mortality and morbidity in the early period after LT. Identifying the risk factors could help in minimizing their development. We prospectively investigated the incidence, characteristics, and risk factors of bacterial infections among the recipients during hospitalization after LT and assigned a predictive score. All 389 consecutive adults who underwent LT at the main referral hospital of LT in Iran during 1 year were enrolled prospectively in a cohort study. Infection group consisted of 143 recipients (36.8%). Urinary tract and surgical site infections were the most frequent ones. Gram-negative bacteria were more prevalent than Gram-positive ones. Independent risk factors were female sex (relative risks = 2.13), age ≤ 43.5 years (3.70), hospital stay ≥ 9.5 days (5.22), abdominal reoperation (3.03), vancomycin-resistant Enterococci colonization (5.52), hospitalization 3 months prior to LT (3.25), mechanical ventilation ≥48 hr (4.93), and renal replacement therapies (13.40). We developed a risk score for the prediction of bacterial infections with an area under the receiver operating characteristic curve of 0.85 (95% CI, 0.81–0.89) with sensitivity of 88% and specificity of 64%. In the infection group, mortality was higher than in controls (18.9% vs. 2.0%) with longer hospitalization (16 vs. 10 days; P < 0.001). We detected a high rate of bacterial infections leading to longer hospital stay and higher mortality rate. The formulated risk score can help predict bacterial infections; however, it requires clinical validation in further studies.     

Tropisetron attenuates tumor growth and progression in an experimental model of mouse lung cancer

The antineoplastic effects of 5-hydroxytryptamine (5-HT) receptor antagonists have been shown in previous studies. However, the exact underlying mechanisms mediating these antineoplastic effects are unclear. In the present study, we assessed the antineoplastic effects of tropisetron, a 5-HT receptor antagonist, in an experimental model of lung cancer in BALB/c mouse. Lewis lung carcinoma cell line was used to induce lung cancer. Mice were divided into four groups (n = 6) as follows: tumor-bearing mice + tropisetron (5 mg/kg intraperitoneally [IP]), tumor-bearing mice + tropisetron (10 mg/kg IP), tumor-bearing mice + saline, healthy mice + tropisetron (10 mg/kg). Tumor burden, interferon-γ (IFN-γ), interleukin (IL)-4, pathological response, Ki-67, and E-cadherin were assessed using enzyme-linked immunosorbent assay, and real-time polymerase chain reaction. Comet assay was used to assess DNA toxicity. Tropisetrone-treated animals (either 5 or 10 mg/kg) showed significantly lower tumor sizes at the day 24th after tumor induction. Tropisetron received animals also showed significantly higher levels of IFN-γ, E-cadherin, pathologic response, and necrotic cells compared to the saline-treated counterparts. In addition, the levels of IL-4, and Ki-67 were significantly lower in tropisetrone treated mice in comparison with control. Furthermore, tropisteron coadministration signifcantly reduced H₂O₂-induced DNA toxicity while treatment with tropisteron alone showed no adverse effect on DNA. Tropisetrone can be used as a potential antineoplastic drug in lung cancer. This agent can promote its antineoplastic effects in part through modulating inflammatory and proliferating markers.     

Effects of human placenta-derived mesenchymal stem cells with NK4 gene expression on glioblastoma multiforme cell lines

Poor prognosis and low survival are commonly seen in patients with glioblastoma multiforme (GBM). Due to the specific nature of solid tumors such as GBM, delivery of therapeutic agents to the tumor sites is difficult. So, one of the major challenges in the treatment of these tumors is a selection of appropriate method for drug delivery. Mesenchymal stem cells (MSCs) have a unique characteristic in migration toward the tumor tissue. In this regard, the present study examined the antitumor effects of manipulating human placenta-derived mesenchymal stem cells (PDMSCs) with NK4 expression (PDMSC-NK4) on GBM cells. After separation and characterization of PDMSCs, these cells were transduced with NK4 which was known as the antagonist of hepatocyte growth factor (HGF). The results indicated that engineered PDMSCs preferably migrate into GBM cells by transwell coculture system. In addition, the proliferation of the GBM cells significantly reduced after coculture with these cells. In fact, manipulated PDMSCs inhibited growth of tumor cells by induction of apoptosis. Our findings suggested that besides having antitumor effects, PDMSCs can also be applied as an ideal cellular vehicle to target the glioblastoma multiforme.