Potential antiplatelet agents with grape seed - backbone polyphenols: computational studies.

The study focused on grape seed-derived polyphenols for their antiplatelet, anti-inflammatory, and fibrinolytic properties through molecular docking and dynamics simulations. Compounds were evaluated for their effects on P2Y12, PTP1B, thromboxane A2, and other targets. Compounds 1 and 6 showed strong inhibitory potential on P2Y12. Compounds 2 and 7, plus epigallocatechin gallate, demonstrated effective inhibition on NF-KB and COX1. The compounds exhibited drug-like properties and potential for new thrombotic disease therapies. The research sheds light on the interactions between polyphenols and target proteins, paving the way for novel antiplatelet strategies.

A systematic approach introduced some immune system targets in rectal cancer by considering cell-free DNA methylation in response to radiochemotherapy.

BACKGROUND: This study aims to investigate cell-free DNA (cfDNA) methylation of genes involved in some immune system targets as biomarkers of radioresistance in patients with non-metastatic rectal cancer. METHODS: Gene expression (GSE68204, GPL6480, and GSE15781) and DNA methylation profiles (GSE75548 and GSE139404) of rectal cancer patients were obtained from the Gene Expression Omnibus (GEO) database. GEO2R and FunRich software were first used to identify genes with significant expression differences. Enricher softwer was then used to analyze Gene Ontology and detect pathway enrichment of hub genes. Blood samples were then taken from 43 rectal cancer patients. After cfDNA extraction from samples, it was treated with bisulfite and analyzed by methylation-specific PCR. RESULTS: 1088 genes with high and 629 with low expression were identified by GEO2R and FunRich software. A total of five high-expression hub genes, including CDH24, FGF18, CCND1, IFITM1, UBE2V1, and three low-expression hub genes, including CBLN2, VIPR2, and IRF4, were identified from UALCAN and DNMIVD databases. Methylation-specific PCR indicated a significant difference in hub gene methylation between cancerous and non-cancerous individuals. Radiochemotherapy significantly affected hub gene methylation. There was a considerable difference in the methylation rate of hub genes between patients who responded to radiochemotherapy and those who did not. CONCLUSIONS: Evaluating gene methylation patterns might be an appropriate diagnostic tool to predict radiochemotherapy response and develop targeted therapeutic agents.

Association of future cancer metastases with fibroblast activation protein-α: a systematic review and meta-analysis.

Introduction: Fibroblast activation protein-α (FAP-α) is a vital surface marker of cancer-associated fibroblasts, and its high expression is associated with a higher tumor grade and metastasis. A systematic review and a meta-analysis were performed to associate future metastasis with FAP-α expression in cancer. Methods: In our meta-analysis, relevant studies published before 20 February 2024 were systematically searched through online databases that included PubMed, Scopus, and Web of Science. The association between FAP-α expression and metastasis, including distant metastasis, lymph node metastasis, blood vessel invasion, vascular invasion, and neural invasion, was evaluated. A pooled odds ratio (OR) with 95% confidence intervals (CI) was reported as the measure of association. Results: A total of 28meta-analysis. The random-effects model for five parameters showed that a high FAP-α expression was associated with blood vessel invasion (OR: 3.04, 95% CI: 1.54-5.99, I 2 = 63%, P = 0.001), lymphovascular invasion (OR: 3.56, 95% CI: 2.14-5.93, I 2 = 0.00%, P < 0.001), lymph node metastasis (OR: 2.73, 95% CI: 1.96-3.81, I 2 = 65%, P < 0.001), and distant metastasis (OR: 2.59; 95% CI: 1.16-5.79, I 2 = 81%, P < 0.001). However, our analysis showed no statistically significant association between high FAP-α expression and neural invasion (OR: 1.57, 95% CI: 0.84-2.93, I 2 = 38%, P = 0.161). Conclusions: This meta-analysis indicated that cancer cells with a high FAP-α expression have a higher risk of metastasis than those with a low FAP-α expression. These findings support the potential importance of FAP-α as a biomarker for cancer metastasis prediction.

Strategy of targeting the tumor microenvironment via inhibition of fibroblast/fibrosis remodeling new era to cancer chemo-immunotherapy resistance.

The use of repurposing drugs that may have neoplastic and anticancer effects increases the efficiency and decrease resistance to chemotherapy drugs through a biochemical and mechanical transduction mechanisms through modulation of fibroblast/fibrosis remodeling in tumor microenvironment (TME). Interestingly, fibroblast/fibrosis remodeling plays a vital role in mediating cancer metastasis and drug resistance after immune chemotherapy. The most essential hypothesis for induction of chemo-immunotherapy resistance is via activation of fibroblast/fibrosis remodeling and preventing the infiltration of T cells after is mainly due to the interference between cytoskeleton, mechanical, biochemical, metabolic, vascular, and remodeling signaling pathways in TME. The structural components of the tumor that can be targeted in the fibroblast/fibrosis remodeling include the depletion of the TME components, targeting the cancer-associated fibroblasts and tumor associated macrophages, alleviating the mechanical stress within the ECM, and normalizing the blood vessels. It has also been found that during immune-chemotherapy, TME injury and fibroblast/fibrosis remodeling causes the up-regulation of inhibitory signals and down-regulation of activated signals, which results in immune escape or chemo-resistance of the tumor. In this regard, repurposing or neo-adjuvant drugs with various transduction signaling mechanisms, including anti-fibrotic effects, are used to target the TME and fibroblast/fibrosis signaling pathway such as angiotensin 2, transforming growth factor-beta, physical barriers of the TME, cytokines and metabolic factors which finally led to the reverse of the chemo-resistance. Consistent to many repurposing drugs such as pirfenidone, metformin, losartan, tranilast, dexamethasone and pentoxifylline are used to decrease immune-suppression by abrogation of TME inhibitory signal that stimulates the immune system and increases efficiency and reduces resistance to chemotherapy drugs. To overcome immunosuppression based on fibroblast/fibrosis remodeling, in this review, we focus on inhibitory signal transduction, which is the physical barrier, alleviates mechanical stress and prevents mechano-metabolic activation.

Neuroprotective effect of Potentilla reptans L. root in the rat brain global ischemia/reperfusion model.

Stroke is the most common cause of death among neurological diseases. The protective effects of Potentilla reptans L. include antioxidative, anti-inflammatory, and antiapoptotic effects. In this study, the brain protection and beta-amyloid effects of P. reptans root extract were investigated in the rat brain ischemia/reperfusion (IR) model. Forty male Wistar rats were randomly divided into five groups (n = 8), including IR, sham, and three groups receiving P. reptans with concentrations of 0.025, 0.05, and 0.1 (g/kg/b.w.), which were injected daily for 7 days. For the IR model, the common carotid artery was occluded bilaterally for 8 min. All injections were intraperitoneal (IP). The shuttle box test was used to measure passive avoidance memory. Then the brain tissue was extracted for the histological examination of neuron counts and ß-amyloid plaques using a morphometric technique, and finally, Statistical Package for the Social Sciences software was used for statistical analysis of the data. Pretreatment with P. reptans improved memory impairment. Also, by examining the tissues of the CA1, CA3, and dentate gyrus areas of the hippocampus, it was observed that the number of plaques in the groups receiving P. reptans extract was reduced compared to the IR group, especially at the concentration of 0.05 g/kg/b.w. Also, P. reptans improved the number of neurons at all concentrations, in which the concentration of 0.05 g/kg/b.w. showed more effective therapeutic results. Taken together, we found that P. reptans root extract has beneficial effects on memory impairment, neuronal loss, and ß-amyloid accumulation.

Folic acid-conjugated dextran-coated Zn0.6Mn0.4Fe2O4 nanoparticles as systemically delivered nano heaters with self-regulating temperature for magnetic hyperthermia therapy of liver tumors.

Successful cancer treatment using magnetic hyperthermia therapy (MHT) strongly depends on biocompatible magnetic nanoparticles (NPs). They can effectively accumulate in tumor tissues after systemic injection and generate heat in the therapeutic temperature range (42-48 °C) by exposure to an AC magnetic field (AMF). For this purpose, folic acid-conjugated dextran-coated Zn0.6Mn0.4Fe2O4 (FA-Dex-ZMF) NPs were synthesized as smart nano heaters with self-regulating temperatures for MHT of liver tumors. Animal studies on BALB/c mice showed that the prepared NPs did not cause acute toxicity upon administration up to 100 mg kg-1. Likewise, no significant changes in hematological and biochemical factors were observed. FA-Dex-ZMF NPs were studied by exposing them to different safe AC magnetic fields (f = 150 kHz, H = 6, 8, and 10 kA m-1). Calorimetric experiments revealed that the NPs reached the desired temperature range (42-48 °C), which was suitable for MHT. Moreover, the efficacy of FA-Dex-ZMF NPs in MHT of liver tumors was investigated in vivo in liver-tumor-bearing mice. The obtained results revealed that the average volume of tumors in the control group increased 2.2 times during the study period. In contrast, the tumor volume remained almost constant during treatment in the MHT group. The results indicated that folic acid-conjugated dextran-coated Zn0.6Mn0.4Fe2O4 NPs with self-regulating temperature could be a promising tool for systemically delivered MHT.

Niosomal Curcumin Suppresses IL17/IL23 Immunopathogenic Axis in Skin Lesions of Psoriatic Patients: A Pilot Randomized Controlled Trial.

Psoriasis (PS) is characterized by hyperplasia of epidermis and infiltration of immune cells in the dermis. A negligible susceptibility of hypodermic permeation for local anti-inflammatory remedies is one of the major causes of medication failures. Although curcumin (CUR) has indicated effectiveness in treatment of inflammation, its successful permeation through the stratum corneum is yet a challenging issue. Therefore, niosome (NIO) nanoparticles were used as curcumin carriers to enhance its delivery and anti-inflammatory effects. Curcumin-niosome (CUR-NIO) formulations were constructed by the thin-film-hydration (TFH) technique and were added to hyaluronic acid and Marine-collagen gel-based formulation. Five mild-to-moderate PS patients (18-60 years) with PASI scores < 30 with symmetrical and similar lesions were included in the study. The prepared formulation (CUR 15 µM) was topically administered for 4 weeks on the skin lesions, in comparison to the placebo. Clinical skin manifestations were monitored and skin punches were obtained for further gene expression analyses. There was a significant reduction in redness, scaling, and an apparent improvement in CUR-NIO-treated group in comparison to the placebo-treated counterpart. The gene expression analyses resulted in significantly downregulation of IL17, IL23, IL22, and TNFα, S100A7, S100A12, and Ki67 in CUR-NIO-treated lesions. Consequently, CUR-NIO could provide therapeutic approaches for the patients with mild-to-moderate PS by suppressing the IL17/IL23 immunopathogenic axis.

Breast tumor metastasis following filgrastim administration due to the SDF-1/CXCR4 pathway.

Filgrastim, a recombinant type of granulocyte-colony stimulating factor (G-CSF), has a high potential to manage chemotherapy-induced leukopenia. It can increase stromal cell-derived factor 1 (SDF-1) which may stimulate C-X-C chemokine receptor type 4 (CXCR4) to migrate bone marrow-derived stem/progenitor cells to the bloodstream. Here, we aimed to investigate in vitro and in vivo effects of filgrastim on cell migration, invasion, and metastasis. A lentivirus vector of the anti-CXCR4 receptor was first used for the CXCR4 knockout. Effects of filgrastim on cell proliferation and migration were then investigated on 4T1 cells by Transwell migration and wound healing assay. At last, the effects of filgrastim on cell metastasis and the possible involved mechanisms have been investigated in a metastatic murine breast tumor. The knockout of the CXCR4 receptor could lead to a decrease in cell proliferation, migration, and invasion of the 4T1 cells. Filgrastim could directly target SDF-1 and upregulate the expression of the CXCR4 receptor. The knockout of the CXCR4 receptor reduced cell metastasis in an animal model of breast cancer. CXCR4 receptor stimulation by the filgrastim-affected pathways is a conserved evolutionary response that could increase cancer cell proliferation and consequent cell metastasis. Our results suggest that the activation of the CXCR4 receptor is a conserved evolutionary response that can increase cell proliferation, migration, and consequent metastasis. It seems that filgrastim may increase the chance of cancer cell metastasis in people continuously receiving it to increase the number of neutrophils. Filgrastim induces the SDF-1/CXCR4 axis on tumor cell growth. SDF-1 and its receptor CXCR4 are vital targets for filgrastim. The CXCR4 can stimulate the PI3K/AKT, NF-κB, and JAK/STAT signaling pathways. The SDF-1/CXCR4 pathway promotes cell chemotaxis and proliferation via MAPKs signaling. It also enhances cell survival, proliferation, and angiogenesis, increasing tumor cell metastasis. The STAT3-mediated inflammation is essential for tumorigenesis processes, and Akt, Wnt, STAT3, and CXCR4 signaling pathways are all correlated. CXCR4 = C-X-C chemokine receptor type 4, SDF-1 = stromal-derived-factor-1, MAPK = mitogen activated protein kinase; NF-κB = nuclear factor-κB, PI3K = phosphoinositide 3-kinase, JAK = Janus kinase, STAT = signal transducer and activator of transcription, PLC = phospholipase C, PKC = Protein kinase C, GRK = G protein-coupled receptor kinase.

Molecular mechanisms underlying the action of carcinogens in gastric cancer with a glimpse into targeted therapy.

BACKGROUND: Gastric cancer imposes a substantial global health burden despite its overall incidence decrease. A broad spectrum of inherited, environmental and infectious factors contributes to the development of gastric cancer. A profound understanding of the molecular underpinnings of gastric cancer has lagged compared to several other tumors with similar incidence and morbidity rates, owing to our limited knowledge of the role of carcinogens in this malignancy. The International Agency for Research on Cancer (IARC) has classified gastric carcinogenic agents into four groups based on scientific evidence from human and experimental animal studies. This review aims to explore the potential comprehensive molecular and biological impacts of carcinogens on gastric cancer development and their interactions and interferences with various cellular signaling pathways. CONCLUSIONS: In this review, we highlight recent clinical trial data reported in the literature dealing with different ways to target various carcinogens in gastric cancer. Moreover, we touch upon other multidisciplinary therapeutic approaches such as surgery, adjuvant and neoadjuvant chemotherapy. Rational clinical trials focusing on identifying suitable patient populations are imperative to the success of single-agent therapeutics. Novel insights regarding signaling pathways that regulate gastric cancer can potentially improve treatment responses to targeted therapy alone or in combination with other/conventional treatments. Preventive strategies such as control of H. pylori infection through eradication or immunization as well as dietary habit and lifestyle changes may reduce the incidence of this multifactorial disease, especially in high prevalence areas. Further in-depth understanding of the molecular mechanisms involved in the role of carcinogenic agents in gastric cancer development may offer valuable information and update state-of-the-art resources for physicians and researchers to explore novel ways to combat this disease, from bench to bedside. A schematic outlining of the interaction between gastric carcinogenic agents and intracellular pathways in gastric cancer H. pylori stimulates multiple intracellular pathways, including PI3K/AKT, NF-κB, Wnt, Shh, Ras/Raf, c-MET, and JAK/STAT, leading to epithelial cell proliferation and differentiation, apoptosis, survival, motility, and inflammatory cytokine release. EBV can stimulate intracellular pathways such as the PI3K/Akt, RAS/RAF, JAK/STAT, Notch, TGF-ß, and NF-κB, leading to cell survival and motility, proliferation, invasion, metastasis, and the transcription of anti-apoptotic genes and pro-inflammatory cytokines. Nicotine and alcohol can lead to angiogenesis, metastasis, survival, proliferation, pro-inflammatory, migration, and chemotactic by stimulating various intracellular signaling pathways such as PI3K/AKT, NF-κB, Ras/Raf, ROS, and JAK/STAT. Processed meat contains numerous carcinogenic compounds that affect multiple intracellular pathways such as sGC/cGMP, p38 MAPK, ERK, and PI3K/AKT, leading to anti-apoptosis, angiogenesis, metastasis, inflammatory responses, proliferation, and invasion. Lead compounds may interact with multiple signaling pathways such as PI3K/AKT, NF-κB, Ras/Raf, DNA methylation-dependent, and epigenetic-dependent, leading to tumorigenesis, carcinogenesis, malignancy, angiogenesis, DNA hypermethylation, cell survival, and cell proliferation. Stimulating signaling pathways such as PI3K/Akt, RAS/RAF, JAK/STAT, WNT, TGF-ß, EGF, FGFR2, and E-cadherin through UV ionizing radiation leads to cell survival, proliferation, and immortalization in gastric cancer. The consequence of PI3K/AKT, NF-κB, Ras/Raf, ROS, JAK/STAT, and WNT signaling stimulation by the carcinogenic component of Pickled vegetables and salted fish is the Warburg effect, tumorigenesis, angiogenesis, proliferation, inflammatory response, and migration.

Innovative targets of the lncRNA-miR-mRNA network in response to low-dose aspirin in breast cancer patients.

This study aimed to investigate innovative targets in breast cancer patients by considering the interaction of the lncRNA-miR-mRNA network in response to low-dose aspirin. The candidate miRs were first taken from the GEO and TCGA databases. Then, the candidate network was constructed using the high-throughput sequencing data. The expression levels of candidate targets were finally measured using Real-Time PCR in luminal A breast cancer patients undergoing aspirin (80 mg daily for three months) and non-aspirin groups during chemotherapy after surgery. The expression levels of TGFß, IL-17, IFNγ, and IL-ß proteins were measured using the ELISA technique. 5 lncRNAs, 12 miRs, and 10 genes were obtained in the bioinformatic phase. A significant expression increase of the candidate tumor suppressor lncRNAs, miRs, and genes and a substantial expression decrease of the candidate onco-lncRNAs, oncomiRs, and oncogenes were achieved after the aspirin consumption. Unlike the non-aspirin group, the expression levels of TGFß, IL-17, IFNγ, and IL-ß proteins were significantly decreased following aspirin consumption. The Kaplan-Meier analysis indicated a longer overall survival rate in the patients after aspirin consumption. Our results showed that the lncRNA-miR-mRNA network might be a significant target for aspirin; their expression changes may be a new strategy with potential efficacy for cancer therapy or prevention.

Novel targets in rectal cancer by considering lncRNA-miRNA-mRNA network in response to Lactobacillus acidophilus consumption: a randomized clinical trial.

We aimed to explore the lncRNA-miR-mRNA network in response to Lactobacillus acidophilus (L. acidophilus) consumption in rectal cancer patients. The candidate miRs were first taken from the GEO and TCGA databases. We constructed the lncRNA-miR-mRNA network using the high-throughput sequencing data. At last, we created a heatmap based on the experimental data to show the possible correlation of the selected targets. The expression levels of selected targets were measured in the samples of 107 rectal cancer patients undergoing placebo and probiotic consumption and 10 noncancerous subjects using Real-Time PCR. Our analysis revealed a group of differentially expressed 12 miRs and 11 lncRNAs, and 12 genes in rectal cancer patients. A significant expression increase of the selected tumor suppressor miRs, lncRNAs, and genes and a substantial expression decrease of the selected oncomiRs, onco-lncRNAs, and oncogenes were obtained after the probiotic consumption compared to the placebo group. There is a strong correlation between some network components, including miR-133b and IGF1 gene, miR-548ac and MSH2 gene, and miR-21 and SMAD4 gene. In rectal cancer patients, L. acidophilus consumption was associated with improved expression of the lncRNA-miR-mRNA network, which may provide novel monitoring and therapeutic approaches.

Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs); where do they stand in tumorigenesis and how they can change the face of cancer therapy?

The tumor microenvironment (TME) and its components have recently attracted tremendous attention in cancer treatment strategies, as alongside the genetic and epigenetic alterations in tumor cells, TME could also provide a fertile background for malignant cells to survive and proliferate. Interestingly, TME plays a vital role in the mediation of cancer metastasis and drug resistance even against immunotherapeutic agents. Among different cells that are presenting in TME, tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) have shown to have significant value in the regulation of angiogenesis, tumor metastasis, and drug-resistance through manipulating the composition as well as the organization of extracellular matrix (ECM). Evidence has shown that the presence of both TAMs and CAFs in TME is associated with poor prognosis and failure of chemotherapeutic agents. It seems that these cells together with ECM form a shield around tumor cells to protect them from the toxic agents and even the adaptive arm of the immune system, which is responsible for tumor surveillance. Given this, targeting TAMs and CAFs seems to be an essential approach to potentiate the cytotoxic effects of anti-cancer agents, either conventional chemotherapeutic drugs or immunotherapies. In the present review, we aimed to take a deep look at the mechanobiology of CAFs and TAMs in tumor progression and to discuss the available therapeutic approaches for harnessing these cells in TME.

Prediction of COVID-19 manipulation by selective ACE inhibitory compounds of Potentilla reptant root: In silico study and ADMET profile.

In the novel SARS-CoV-2 (COVID-19) as a global emergency event, the main reason of the cardiac injury from COVID-19 is angiotensin-converting enzyme 2 (ACE2) targeting in SARS-CoV-2 infection. The inhibition of ACE2 induces an increase in the angiotensin II (Ang II) and the angiotensin II receptor type 1 (AT1R) leading to impaired cardiac function or cardiac inflammatory responses. The ethyl acetate fraction of Potentilla reptans L. root can rescue heart dysfunction, oxidative stress, cardiac arrhythmias and apoptosis. Therefore, isolated components of P. reptans evaluated to identify natural anti-SARS-CoV-2 agents via molecular docking. In silico molecular docking study were carried out using the Auto Dock software on the isolated compounds of Potentilla reptans root. The protein targets of selective ACE and others obtained from Protein Data Bank (PDB). The best binding pose between amino acid residues involved in active site of the targets and compounds was discovered via molecular docking. Furthermore, ADMET properties of the compounds were evaluated. The triterpenoids of P. reptans showed more ACE inhibitory potential than catechin in both domains. They were selective on the nACE domain, especially compound 5. Also, the compound 5 & 6 had the highest binding affinity toward active site of nACE, cACE, AT1R, ACE2, and TNF-α receptors. Meanwhile, compound 3 showed more activity to inhibit TXA2. Drug likeness and ADMET analysis showed that the compounds passed the criteria of drug likeness and Lipinski rules. The current study depicted that P. reptans root showed cardioprotective effect in COVID-19 infection and manipulation of angiotensin II-induced side effects.

An innovative systematic approach introduced the involved lncRNA-miR-mRNA network in cell cycle and proliferation after conventional treatments in breast cancer patients.

The present study aimed to explore the involved lncRNA-miRNA-mRNA network in the cell cycle and proliferation after conventional treatments in Luminal A breast cancer patients.The candidate miRNAs (miRs), lncRNAs, and mRNAs were first taken from the Gene Expression Omnibus and TCGA databases. The lncRNA-miR-mRNA network was then constructed using the high-throughput sequencing data. The expression levels of selected targets were measured in the breast cancer and healthy samples by the Real-Time PCR technique and compared with the clinical outcomes by the Kaplan-Meier method.Our analysis revealed a group of differentially expressed 3 lncRNAs, 9 miRs, and 14 mRNAs in breast cancer patients. A significant expression decrease of the selected tumor suppressor lncRNAs, miRs, and genes and a substantial expression increase of the selected onco-lncRNAs, oncomiRs, and oncogenes were obtained in the patients compared to the healthy group. The plasma levels of the lncRNAs, miRs, and mRNAs were more significant after the operation, chemotherapy, and radiotherapy than the pre-treatment. The Kaplan-Meier analysis indicated that the patients with a high expression of miR-21, miR-20b, IGF1R, and E2F2 and a low expression of miR-125a, PDCD4, and PTEN had exhibited a shorter overall survival rate.Our results suggested that the underlying mechanisms of the lncRNA, miRs, and mRNAs and relevant signaling pathways may be considered predictive and therapeutic targets for breast cancer.

The other side of the coin: Positive view on the role of opioids in cancer.

Opioids have been used for medicinal purposes as an analgesic and recreational purposes as a euphorigenic throughout human history. Cancer patients are often treated with different doses of opioids concurrently with anti-cancer drugs for pain relief without exhibiting excessive adverse effects. The intersection of the biology of pain, opioid therapy, and disease progression represents the crux of the matters and is of potentially great importance in cancer care. For more than 20 years, multiple investigations have focused on the stimulatory effects of opioids on cancer cell growth, while in-depth studies on the inhibitory effects on cancer cell growth development have usually been neglected. This paper reviews the evidence regarding opioid therapies and their anti-cancer effects on various malignancies. Likewise, we have a glimpse into the molecular mechanisms necessary for pinpointing their positive or negative impacts on malignancies to raise awareness and stimulate more excellent dialogue regarding their carcinogenic/anticarcinogenic roles.

Six new triterpenoids from the root of Potentilla reptans and their cardioprotective effects in silico.

Tormentic acid ester glucosides derivatives (1, 2 and 4), 3-oxoursane ester glycoside (3) and 11-methoxy-ursane ester glycosides (5, 6) as six new triterpenoids, along with catechin were isolated from the ethyl acetate fraction of Potentilla reptans root (Et) methanolic extract. The structures of the compounds were elucidated by 1D, 2D NMR, IR and MS spectroscopy. Additionally, isolated triterpenoid compounds (1-6) and catechin were evaluated for their cardioprotective effects via glycogen synthase kinase 3ß (GSK-3ß) and glucocorticoid regulated kinase-1 (SGK1) protein kinase inhibition by Molecular Docking. Compound 1 and catechin (compound 7) exhibited significant inhibitory effects against GSK-3ß and SGK1 protein kinases with a binding energy value -9.1 and -8.8 kcal/mol, respectively. Hence, Et can be a suitable natural candidate to protect cardiomyocytes injury.

A systematic approach introduced novel targets in rectal cancer by considering miRNA/mRNA interactions in response to radiotherapy.

BACKGROUND: The discovery of miRNA/mRNA interactions in several biological samples prompted the researchers to explore new biomarkers in tumors. OBJECTIVE: We aimed to investigate the interactions of miRNA/mRNA in response to radiotherapy in the plasma samples of rectal cancer patients. METHODS: Five microarray datasets related to cancerous and non-cancerous individuals were first used to construct networks. The databases of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were applied to analyze pathway enrichment. The plasma samples were then collected from 55 patients with recently diagnosed rectal cancer and 10 healthy subjects. For radiotherapy courses, the patients have consecutively received 30 sessions of local radiation for six weeks. At last, the expression of selected genes and miRNAs was experimentally measured before and after radiotherapy by qPCR, and the protein levels of the target genes were measured by ELISA assay. We evaluated the therapeutic responses based on the tumor regression grade of the Dworak classification. RESULTS: We identified 5 up-regulated and 5 down-regulated miRNAs and 8 up-regulated and 3 down-regulated genes of the databases. There was a significant increase in tumor suppressor miRNAs, including miR-101-3p, miR-145-5p, miR-26a-5p, miR-34a-5p, and a significant decrease in oncomiRs, including miR-221-3p and miR-17-5p, after radiotherapy compared to the pre-treatment. Moreover, the up-regulated miR-17-5p and miR-221-5p and the down-regulated miR-101-3p and miR-145-5p were directly related to rectal cancer through the interaction with the Wnt, RAS, PI3K, and TGF-ß signaling pathways. An analysis of receiver operating characteristics showed that miRNAs 221, 17, and 23 were response-related in locally advanced rectal cancer patients. CONCLUSIONS: It seems that monitoring the miRNA/mRNA interactions during radiotherapy can be an appropriate diagnostic tool to track the recovery process and respond to standard therapies.

Potentilla reptans L. postconditioning protects reperfusion injury via the RISK/SAFE pathways in an isolated rat heart.

BACKGROUND: Our previous study indicated that Potentilla reptans root has a preconditioning effect by its antioxidant and anti-apoptotic effects in an isolated rat heart ischemia/reperfusion (IR) model. In the present study, we investigated the post-conditioning cardio-protective effects of Potentilla reptans and its active substances. METHODS: The ethyl acetate fraction of P. reptans root (Et) was subjected to an IR model under 30 min of ischemia and 100 min of reperfusion. To investigate the postconditioning effect, Et was perfused for 15 min at the early phase of reperfusion. RISK/SAFE pathway inhibitors, 5HD and L-NAME, were applied individually 10 min before the ischemia, either alone or in combination with Et during the early reperfusion phase. The hemodynamic factors and ventricular arrhythmia were calculated during the reperfusion. Oxidative stress, apoptosis markers, GSK-3ß and SGK1 proteins were assessed at the end of experiments. RESULTS: Et postconditioning (Etpost) significantly reduced the infarct size, arrhythmia score, ventricular fibrillation incidence, and enhanced the hemodynamic parameters by decreasing the MDA level and increasing expression of Nrf2, SOD and CAT activities. Meanwhile, Etpost increased the BCl-2/BAX ratio and decreased Caspase-3 expression. The cardioprotective effect of Etpost was abrogated by L-NAME, Wortmannin (a PI3K/Akt inhibitor), and AG490 (a JAK/STAT3 inhibitor). Finally, Etpost reduced the expression of GSK-3ß and SGK1 proteins pertaining to the IR group. CONCLUSION: P. reptans reveals the post-conditioning effects via the Nrf2 pathway, NO release, and the RISK/SAFE pathway. Also, Etpost decreased apoptotic indexes by inhibiting GSK-3ß and SGK1 expressions. Hence, our data suggest that Etpost can be a suitable natural candidate to protect cardiomyocytes during reperfusion injury.