Tannic acid is a chief gallo-tannin belonging to the hydrolysable tannins extracted from gall nuts and other plant sources. A myriad of pharmaceutical and biological applications in the medical field ...has been well recognized to tannic acid. Among these effects, potential anticancer activities against several solid malignancies such as liver, breast, lung, pancreatic, colorectal and ovarian cancers have been reported. Tannic acid was found to play a maestro-role in tuning several oncological signaling pathways including JAK/STAT, RAS/RAF/mTOR, TGF-β1/TGF-β1R axis, VEGF/VEGFR and CXCL12/CXCR4 axes. The combinational beneficial effects of tannic acid with other conventional chemotherapeutic drugs have been clearly demonstrated in literature such as a synergistic anticancer effect and enhancement of the chemo-sensitivity in several resistant cases. Yet, clinical applications of tannic acid have been limited owing to its poor lipid solubility, low bioavailability, off-taste, and short half-life. To overcome such obstacles, novel drug delivery systems have been employed to deliver tannic acid with the aim of improving its applications and/or efficacy against cancer cells. Among these drug delivery systems are several types of organic and metallic nanoparticles. In this review, the authors focus on the molecular mechanisms of tannic acid in tuning several neoplastic diseases as well as novel drug delivery systems that can be used for its clinical applications with an attempt to provide a systemic reference to promote the development of tannic acid as a cheap drug and/or drug delivery system in cancer management.
This study aimed to unravel the regulatory role of noncoding RNAs (ncRNA) on the nitric oxide (NO) machinery system in triple‐negative breast cancer (TNBC) patients and to further assess the ...influence of NO‐modulating ncRNAs on TNBC progression, immunogenic profile, and the tumor microenvironment (TME). The results revealed miR‐939‐5p and lncRNA HEIH as novel ncRNAs modulating NO machinery in TNBC. MiR‐939‐5p, an underexpressed microRNA (miRNA) in BC patients, showed an inhibitory effect on NOS2 and NOS3 transcript levels on TNBC cells. In contrast, HEIH was found to be markedly upregulated in TNBC patients and showed a modulatory role on miR‐939‐5p/NOS2/NO axis. Functionally, miR‐939‐5p was characterized as a tumor suppressor miRNA while HEIH was categorized as a novel oncogenic lncRNA in TNBC. Finally, knocking down of HEIH resulted in improvement of immunogenic profile of TNBC cells through inducing MICA/B and suppressing the immune checkpoint inhibitor PDL1. In the same context, knockdown of HEIH resulted in the alleviation of the immune‐suppressive TME by repressing interleukin‐10 and tumor necrosis factor‐α levels. In conclusion, this study identifies miR‐939‐5p as a tumor suppressor miRNA while HEIH as an oncogenic lncRNA exhibiting its effect through miR‐939‐5p/NOS2/NO axis. Therefore, repressing BC hallmarks, improving TNBC immunogenic profile, and trimming TME.
This study aimed to unravel the regulatory role of noncoding RNAs on the nitric oxide (NO) machinery system in triple‐negative breast cancer (TNBC) patients and to further assess the influence of NO‐modulating ncRNAs on TNBC progression, immunogenic profile, and the tumor microenvironment (TME).
Breast cancer (BC) is a highly complex and heterogenous disease. Several oncogenic signaling pathways drive BC oncogenic activity, thus hindering scientists to unravel the exact molecular ...pathogenesis of such multifaceted disease. This highlights the urgent need to find a key regulator that tunes up such intertwined oncogenic drivers to trim the malignant transformation process within the breast tissue. The Insulin-like growth factor (IGF) signaling pathway is a tenacious axis that is heavily intertwined with BC where it modulates the amplitude and activity of vital downstream oncogenic signaling pathways. Yet, the complexity of the pathway and the interactions driven by its different members seem to aggravate its oncogenicity and hinder its target-ability. In this review, the authors shed the light on the stubbornness of the IGF signaling pathway and its potential regulation by non-coding RNAs in different BC subtypes. Nonetheless, this review also spots light on the possible transport systems available for efficient delivery of non-coding RNAs to their respective targets to reach a personalized treatment code for BC patients.
Age and Gender are vital determinants for the micronutrient demands of normal indviduals. Among these micronutrients are vitamins that are required in small amounts for optimum metabolism, ...homeostasis, and a healthy lifestyle, acting as coenzymes in several biochemical reactions. The majority of previous studies have examined such issues that relates to a specific vitamin or life stage, with the majority merely reporting the effect of either excess or deficiency. Vitamins are classified into water-soluble and fat-soluble components. The fat-soluble vitamins include vitamins (A, D, E, and K). Fat-soluble vitamins were found to have an indisputable role in an array of physiological processes such as immune regulation, vision, bone and mental health. Nonetheless, the fat-soluble vitamins are now considered a prophylactic measurement for a multitude of diseases such as autism, rickets disease, gestational diabetes, and asthma. Herein, in this review, a deep insight into the orchestration of the four different fat-soluble vitamins requirements is presented for the first time across the human life cycle beginning from fertility, pregnancy, adulthood, and senility with an extensive assessment ofthe interactions among them and their underlying mechanistic actions. The influence of sex for each vitamin is also presented at each life stage to highlight the different daily requirements and effects.
Triple negative breast cancer (TNBC) is known as hot immunogenic tumor. Yet, it is one of the most aggressive BC subtypes. TNBC evolve several tactics to evade the immune surveillance phenomena, one ...of which is shedding of natural killer (NK) cells activating immune ligands such as MICA/B and/or by inducing the expression of the immune checkpoints such as PD-L1 and B7-H4. MALAT-1 is an oncogenic lncRNA. MALAT-1 immunogenic profile is not well investigated.
The study aims at exploring the immunogenic role of MALAT-1 in TNBC patients and cell lines and to identify its molecular mechanism in altering both innate and adaptive immune cells present at the tumor microenvironment of TNBC
BC patients (n = 35) were recruited. Primary NK cells and cytotoxic T lymphocytes were isolated from normal individuals using the negative selection method. MDA-MB-231 cells were cultured and transfected by several oligonucleotides by lipofection technique. Screening of ncRNAs was performed using q-RT-PCR. Immunological functional analysis experiments were performed upon co-culturing primary natural killer cells and cytotoxic T lymphocytes using LDH assay. Bioinformatics analysis was performed to identify potential microRNAs targeted by MALAT-1.
MALAT-1 expression was significantly upregulated in BC patinets with a profound expression in TNBC patients compared to their normal counterparts. Correlation analysis revealed a positive correlation between MALAT-1, tumor size and lymph node metastasis. Knocking down of MALAT-1 in MDA-MB-231 cells resulted in a significant induction of MICA/B, repression of PD-L1 and B7-H4 expression levels. Enhancement of cytotoxic activity of co-cultured NK and CD8+ cells with MALAT-1 siRNAs transfected MDA-MB-231 cells. In silico analysis revealed that miR-34a and miR-17–5p are potential targets to MALAT-1; accordingly, they were found to be downregulated in BC patients. Forcing the expression of miR-34a in MDA-MB-231 cells resulted in a significant induction in MICA/B levels. Ectopic expression of miR-17–5p in MDA-MB-231 cells significantly repressed the expression of PD-L1 and B7-H4 checkpoints. Validations of MALAT-1/miR-34a" and "MALAT-1/miR-17–5p axes were performed by a series of co-transfections and functional assessment of cytotoxic profile of primary immune cells.
This study proposes a novel epigenetic alteration exerted by TNBC cells mainly by inducing the expression of MALAT-1 lncRNA. MALAT-1 mediates innate and adaptive immune suppression events partially via targeting miR-34a/MICA/B and miR-175p/PD-L1/B7-H4 axes in TNBC patients and cell lines.
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Chemotherapy is still the mainstay of treatment for triple-negative breast cancer (TNBC) patients. Yet only 20% of TNBC patients show a pathologic complete response (pCR) after neoadjuvant ...chemotherapy. 5-Fluorouracil (5-FU) is a stable cornerstone in all recommended chemotherapeutic protocols for TNBC patients. However, TNBC patients' innate or acquired chemoresistance rate for 5-FU is steeply escalating. This study aims to unravel the mechanism behind the chemoresistance of 5-FU in the aggressive TNBC cell line, MDA-MB-231 cells, to explore further the role of the tumor suppressor microRNAs (miRNAs), miR-1275, miR-615-5p, and Let-7i, in relieving the 5-FU chemoresistance in TNBC, and to finally provide a translational therapeutic approach to co-deliver 5-FU and the respective miRNA oligonucleotides using chitosan-based nanoparticles (CsNPs). In this regard, cellular viability and proliferation were investigated using MTT and BrdU assays, respectively. 5-FU was found to induce JAK/STAT and PI3K/Akt/mTOR pathways in MDA-MB-231 cells with contaminant repression of their upstream regulators miR-1275, miR-615-5p, and Let-7i. Moreover, CsNPs prepared using the ionic gelation method were chosen and studied as nanovectors of 5-FU and a combination of miRNA oligonucleotides targeting TNBC. The average particle sizes, surface charges, and morphologies of the different CsNPs were characterized using dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. In addition, the encapsulation efficiency (EE%), drug loading capacity (DLC%), and release manner at two different pH values were assessed. In conclusion, the novel CsNPs co-loaded with 5-FU and the combination of the three miRNA oligonucleotides demonstrated synergistic activity and remarkable repression in cellular viability and proliferation of TNBC cells through alleviating the chemoresistance to 5-FU.
Triple‐negative breast cancer (TNBC) represents an aggressive breast cancer subtype. Among young females, TNBC is the leading cause of cancer‐related mortalities. Recently, long noncoding RNAs ...(lncRNAs) are representing a promising pool of regulators for tuning the aggressiveness of several solid malignancies. However, this still needs further investigations in TNBC. The main aim of this study is to unravel the expression pattern of sONE lncRNA and its mechanistic role in TNBC. Results showed that sONE is restrictedly expressed in TNBC patients; its expression level is inversely correlated with the aggressiveness of the disease. sONE acts as a posttranscriptional regulator to endothelial nitric oxide synthase (eNOS) and thus affecting eNOS‐induced nitric oxide (NO) production from TNBC cells measured by Greiss reagent. Mechanistically, sONE is a potential tumor suppressor lncRNA in TNBC cells; repressing cellular viability, proliferation, colony‐forming ability, migration, and invasion capacities of MDA‐MB‐231. Furthermore, sONE effects were found to be extended to affect the maestro tumor suppressor TP53 and the oncogenic transcription factor c‐Myc. Knocking down of sONE resulted in a marked decrease in TP53 and increase in c‐Myc and consequently altering the expression status of their downstream tumor suppressor microRNAs (miRNAs) such as miR‐34a, miR‐15, miR‐16, and let‐7a. In conclusion, this study highlights sONE as a downregulated tumor suppressor lncRNA in TNBC cells acting through repressing eNOS‐induced NO production, affecting TP53 and c‐Myc proteins levels and finally altering the levels of a panel of tumor suppressor miRNAs downstream TP53/c‐Myc proteins.
sONE is a novel tumor suppressor long noncoding RNA (lncRNA) in triple‐negative breast cancer (TNBC). sONE lncRNA is restrictively expressed in TNBC patients. sONE expression level is inversely correlated with the aggressiveness of the disease. sONE expression level is almost diminished in young TNBC patients.
Triple-Negative Breast Cancer (TNBC) is one of the most aggressive and hot BC subtypes. Our research group has recently shed the light on the utility of natural compounds as effective ...immunotherapeutic agents. The aim of this study is to investigate the role of a methoxylated quercetin glycoside (MQG) isolated from
Cleome droserifolia
in harnessing TNBC progression and tuning the tumor microenvironment and natural killer cells cytotoxicity. Results showed that MQG showed the highest potency (IC
50
= 12 µM) in repressing cellular proliferation, colony-forming ability, migration, and invasion capacities. Mechanistically, MQG was found to modulate a circuit of competing endogenous RNAs where it was found to reduce the oncogenic MALAT-1 lncRNA and induce TP53 and its downstream miRNAs; miR-155 and miR-146a. Accordingly, this leads to alteration in several downstream signaling pathways such as nitric oxide synthesizing machinery, natural killer cells' cytotoxicity through inducing the expression of its activating ligands such as MICA/B, ULBP2, CD155, and ICAM-1 and trimming of the immune-suppressive cytokines such as TNF-α and IL-10. In conclusion, this study shows that MQG act as a compelling anti-cancer agent repressing TNBC hallmarks, activating immune cell recognition, and alleviating the immune-suppressive tumor microenvironment experienced by TNBC patients.
Triple Negative Breast Cancer (TNBC) immunotherapy has recently shown promising approach. However, some TNBC patients presented with resistance. One of the reasons was attributed to the excessive ...release of cytokines at the tumor microenvironment (TME) such as Tumor necrosis factor alpha (TNF-α) and Interleukin-10 (IL-10). Fine regulation of these cytokines’ levels via non-coding RNAs (ncRNAs) might alleviate the immune quiescent nature of TME at TNBC tumors. However, the extrapolation of ncRNAs as therapeutic tools is highly challenging. Therefore, disentanglement the nature for the isolation of natural compounds that could modulate the ncRNAs and their respective targets is an applicable translational therapeutic approach. Hence, this study aimed to targeting the chief immune suppressive cytokines at the TME (TNF-α and IL-10) via ncRNAs and to examine the effects of Rosemary aerial parts extract on the expression levels of these ncRNAs in TNBC. Results revealed miR-17-5p as a dual regulator of TNF-α and IL-10. Moreover, an intricate interaction has been shown between miR-17-5p and the oncogenic lncRNAs: MALAT1 and H19. Knocking down of MALAT1 and/or H19 caused an induction in miR-17-5p and reduction in TNF-α and IL-10 expression levels. miR-17-5p was found to be down-regulated, while TNF-α, IL-10, MALAT1 and H19 were up-regulated in BC patients. Forced expression of miR-17-5p in MDA-MB-231 cells reduced TNF-α, IL-10, MALAT1 and H19 expression levels, as well as several BC hallmarks. In a translational approach, ursolic acid (UA) isolated from rosemary induced the expression of miR-17-5p, MALAT1 and decreased H19 expression levels. In conclusion, this study suggests miR-17-5p as a tumor suppressor and an immune-activator miRNA in BC through tuning up the immunological targets TNF-α, IL-10 at the TME and the oncological mediators MALAT1 and H19 lncRNAs.
•Tumor-associated macrophages (TAMs) limit PDT efficacy in melanoma.•Phoenix dactylifera L. (Sukkari date fraction) promoted the repolarization of TAMs from the pro-tumor M2 into the anti-tumor M1 ...phenotype.•The secretome of Phoenix dactylifera L.-repolarized M1 TAMs significantly reduced the required PDT IC50 in melanoma cells.•Phoenix dactylifera L. (Sukkari date fraction) is superior to resiquimod in terms of TAM repolarization and enhancement of PDT efficiency.•Phoenix dactylifera L. (Sukkari date fraction) improved PDT efficacy in melanoma possibly through H19/iNOS/PD-L1 axis.
The tumor microenvironment (TME) represents a barrier to PDT efficacy among melanoma patients. The aim of this study is to employ a novel muti-tactic TME-remodeling strategy via repolarization of tumor-associated macrophages (TAMs), the main TME immune cells in melanoma, from the pro-tumor M2 into the antitumor M1 phenotype using Phoenix dactylifera L. (date palm) in combination with PDT.
Screening of different date cultivars was employed to choose extracts of selective toxicity to melanoma and TAMs, not normal macrophages. Potential extracts were then fractionated and characterized by gas chromatography-mass spectrometry (GC-MS). Finally, the efficacy and the potential molecular mechanism of the co-treatment were portrayed via quantitative real-time polymerase chain reaction (qRT-PCR) analysis.
Initial screening resulted in the selection of the two Phoenix dactylifera L. cultivars Safawi and Sukkari methanolic extracts. Sukkari showed superior capacity to revert TAM phenotype into M1 as well as more prominent upregulation of M1 markers and repression of melanoma immunosuppressive markers relative to positive control (resiquimod). Molecularly, it was shown that PDT of melanoma cells in the presence of the secretome of repolarized TAMs surpassed the monotherapy via the modulation of the H19/iNOS/PD-L1immune-regulatory axis.
This study highlights the potential utilization of nutraceuticals in combination with PDT in the treatment of melanoma to provide a dual activity through alleviating the immune suppressive TME and potentiating the anti-tumor responses.
Abbreviations; cv, cultivar; TAM; tumor-associated macrophage; Ce6-NP; chlorin e-6 nanoparticles; IL-, interleukin; iNOS, inducible nitric oxide synthase; PD-L1, programmed death-ligand 1; PDT, photodynamic therapy. Display omitted
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