In vitro and in vivo evaluation of the diabetic wound healing properties of Saffron (Crocus Sativus L.) petals.

Wound healing is a complex process orchestrated by interactions between a variety of cell types, including keratinocytes, fibroblasts, endothelial cells, inflammatory cells, and bioactive factors such as extracellular matrix (ECM) components, growth factors, and cytokines. Chronic wounds exhibit delayed proliferative phase initiation, reduced angiogenesis, impaired ECM synthesis, and persistent inflammatory response. Chronic wounds are one of the main challenges to the healthcare system worldwide, with a high cost for medical services. Hence, investigation of new approaches to accelerate wound healing is essential. Phytomedicines are considered as potential agents for improving the wound healing by accelerating epithelization, collagen synthesis, and angiogenesis. These natural compounds have various advantages including availability, ease of application, and high effectiveness in wound managment. This study aimed to investigate the biological effects of saffron or Crocus sativus L. (C. sativus) petal extract on cell survival, migration, and angiogenesis using MTT, scratch and in vitro tube formation assays. Moreover, the expression of collagen type I alpha 1 (COL1A1) and vascular endothelial growth factor (VEGF) were evaluated in human dermal fibroblasts (HDF)s and human umbilical vein endothelial cells (HUVEC)s, respectively. The effect of the C. sativus extract on the skin of diabetic mice was also monitored. The results showed that C. sativus petal extract promoted the viability and migration of HDFs and HUVECs. Moreover, C. sativus petal extract enhanced the formation of tube-like structures by HUVECs cultured on the Matrigel basement membrane matrix, indicating its potential to stimulate angiogenesis. Gene expression studies have shown the the C. sativus extract increases wound healing by upregulation of COL1A1 and VEGF, which are crucial factors involved in collagen deposition, epithelialization, and angiogenesis. Histological analysis revealed that C. sativus petal extract enhanced vascularity and increased the number of fibroblasts and collagen synthesis, ultimately accelerating wound closure compared to wounds treated with eucerin and commercial ointment in diabetic mice. Therefore, C. sativus petal extract has potential as a herbal treatment to improve the healing of diabetic wounds.

Angio-microRNAs in diabetic foot ulcer-: Mechanistic insights and clinical perspectives.

Diabetic foot ulcers, as one of the chronic wounds, are a serious challenge in the global healthcare system which have shown notable growth in recent years. DFU is associated with impairment in various stages of wound healing, including angiogenesis. Aberrant expression of microRNAs (miRNAs) involved in the disruption of the balance between angiogenic and anti-angiogenic factors, plays a crucial role in angiogenesis dysfunction. Alteration in the expression of angiomiRNAs (angiomiRs) have the potential to function as biomarkers in chronic wounds. Additionally, considering the rising importance of therapeutic RNAs, there is potential for utilizing angiomiRs in wound healing to induce angiogenesis. This review aims to explore angiogenesis in chronic wounds and investigate the mechanisms mediated by pro- and anti-angiomiRs in the context of diabetic foot ulcers.

Exosomes in skin photoaging: biological functions and therapeutic opportunity.

Exosomes are tiny extracellular vesicles secreted by most cell types, which are filled with proteins, lipids, and nucleic acids (non-coding RNAs, mRNA, DNA), can be released by donor cells to subsequently modulate the function of recipient cells. Skin photoaging is the premature aging of the skin structures over time due to repeated exposure to ultraviolet (UV) which is evidenced by dyspigmentation, telangiectasias, roughness, rhytides, elastosis, and precancerous changes. Exosomes are associated with aging-related processes including, oxidative stress, inflammation, and senescence. Anti-aging features of exosomes have been implicated in various in vitro and pre-clinical studies. Stem cell-derived exosomes can restore skin physiological function and regenerate or rejuvenate damaged skin tissue through various mechanisms such as decreased expression of matrix metalloproteinase (MMP), increased collagen and elastin production, and modulation of intracellular signaling pathways as well as, intercellular communication. All these evidences are promising for the therapeutic potential of exosomes in skin photoaging. This review aims to investigate the molecular mechanisms and the effects of exosomes in photoaging.

Current concepts of microRNA-mediated regulatory mechanisms in human pulp tissue-derived stem cells: a snapshot in the regenerative dentistry.

One of the most studied class of non-coding RNAs is microRNAs (miRNAs) which regulate more than 60% of human genes. A network of miRNA gene interactions participates in stem cell self-renewal, proliferation, migration, apoptosis, immunomodulation, and differentiation. Human pulp tissue-derived stem cells (PSCs) are an attractive source of dental mesenchymal stem cells (MSCs) which comprise human dental pulp stem cells (hDPSCs) obtained from the dental pulp of permanent teeth and stem cells isolated from exfoliated deciduous teeth (SHEDs) that would be a therapeutic opportunity in stomatognathic system reconstruction and repair of other damaged tissues. The regenerative capacity of hDPSCs and SHEDs is mediated by osteogenic, odontogenic, myogenic, neurogenic, angiogenic differentiation, and immunomodulatory function. Multi-lineage differentiation of PSCs can be induced or inhibited by the interaction of miRNAs with their target genes. Manipulating the expression of functional miRNAs in PSCs by mimicking miRNAs or inhibiting miRNAs emerged as a therapeutic tool in the clinical translation. However, the effectiveness and safety of miRNA-based therapeutics, besides higher stability, biocompatibility, less off-target effects, and immunologic reactions, have received particular attention. This review aimed to comprehensively overview the molecular mechanisms underlying miRNA-modified PSCs as a futuristic therapeutic option in regenerative dentistry.

Exosomes derived from cancer-associated fibroblasts mediate response to cancer therapy.

Cancer-associated fibroblasts (CAFs) are the prominent stromal cell population in the tumor microenvironment (TME), which play an indispensable role in cancer progression and response to therapy. CAFs provide communication between tumor cells and surrounding cells by secreting soluble biomolecules and extracellular vesicles (EVs). Exosomes are small membrane-bound EVs that contain various cargos, including growth factors, non-coding RNAs (ncRNAs), cytokines, and chemokines. These biomolecules can be transferred between cells within the TME and alter the behavior of recipient cells. Some studies have shown that exosomes secreted by CAFs contribute to resistance to chemotherapy and radiotherapy. This review focuses on CAF-derived exosomes in different types of tumors, with emphasis on resistance to chemotherapy and radiotherapy.

Wound dressings incorporating microRNAs: Innovative therapy for diabetic wound treatment.

Diabetic wounds are the most critical complication in patients with diabetes, which often lead to hospitalization and limb amputations. Diabetic foot ulcers (DFU) is characterized by infections, prolonged inflammation, and a delayed wound healing process. Different types of medical procedures including surgical therapy, drug delivery, stem cell therapy, and wound dressings are used to manage DFU. Bioactive dressings such as hydrogels, nanofiber, and collagens are promising materials that can accelerate the healing process. The wound dressing materials can also be loaded with bioactive molecules like nucleic acids. MicroRNAs (miRNAs) are small non-coding RNA molecules that have recently emerged as regulators of impaired wound healing and could be a target for DFU treatment. miRNA therapeutics can be delivered to the wound region using different delivery systems such as exosomes and nanoparticles. These wound dressings have a high potential for treating diabetic wounds by topical delivery of certain miRNAs in a sustained release manner.

Angioregulatory microRNAs in breast cancer: Molecular mechanistic basis and implications for therapeutic strategies.

Background: Cancer-associated angiogenesis is a fundamental process in tumor growth and metastasis. A variety of signaling regulators and pathways contribute to establish neovascularization, among them as small endogenous non-coding RNAs, microRNAs (miRNAs) play prominent dual regulatory function in breast cancer (BC) angiogenesis. Aim of Review: This review aims at describing the current state-of-the-art in BC angiogenesis-mediated by angioregulatory miRNAs, and an overview of miRNAs dysregulation association with the anti-angiogenic response in addition to potential clinical application of miRNAs-based therapeutics. Key Scientific Concepts of Review: Angioregulatory miRNA-target gene interaction is not only involved in sprouting vessels of breast tumors but also, trans-differentiation of BC cells to endothelial cells (ECs) in a process termed vasculogenic mimicry. Using canonical and non-canonical angiogenesis pathways, the tumor cell employs the oncogenic characteristics such as miRNAs dysregulation to increase survival, proliferation, oxygen and nutrient supply, and treatment resistance. Angioregulatory miRNAs in BC cells and their microenvironment have therapeutic potential in cancer treatment. Although, miRNAs dysregulation can serve as tumor biomarker nevertheless, due to the association of miRNAs dysregulation with anti-angiogenic resistant phenotype, clinical benefits of anti-angiogenic therapy might be challenging in BC. Hence, unveiling the molecular mechanism underlying angioregulatory miRNAs sparked a booming interest in finding new treatment strategies such as miRNA-based therapies in BC.

Non-coding RNAs in photoaging-related mechanisms: a new paradigm in skin health.

The aging of skin is a biological process affected by environmental or genetic factors. Exposure to ultraviolet (UV) radiation is the main environmental factor causing skin aging. Cumulative UV-induced photodamage of the skin tissue is associated with premature cellular senescence, extracellular degradation, and inflammatory responses in photoaging processes. Non-coding RNAs (ncRNAs) are untranslated transcripts and master regulators of protein-coding genes. ncRNAs have a critical regulatory role in maintaining skin structure, skin barrier function, morphogenesis, and development. Altered ncRNA expression has been reported in various skin disorders such as photoaging and skin cancers. ncRNAs contribute to the suppression and promotion of photoaging by modulating signaling pathways such as mitogen-activated protein kinase (MAPK) pathway and regulating inflammatory cytokines, matrix metalloproteinases (MMPs), and senescence-associated genes. Elucidation of the functions of ncRNAs will improve the identification of molecular mechanisms underlying photoaging, and can be used in the development of therapeutic approaches in skin health and prevention of sun-induced aging. This review summarized the currently described ncRNAs and their functions in photoaging.

Role of non-coding RNAs in response of breast cancer to radiation therapy.

Breast cancer ranks as the first common cancer with a high incidence rate and mortality among women. Radiation therapy is the main therapeutic method for breast cancer patients. However, radiation resistance of tumor cells can reduce the efficacy of treatment and lead to recurrence and mortality in patients. Non-coding RNA (ncRNAs) refers to a group of small RNA molecules that are not translated into protein, while they have the ability to modulate the translation of target mRNA. Several studies have reported the altered expression of ncRNAs in response to radiation in breast cancer. NcRNAs have been found to influence on radiation response of breast cancer by regulating various mechanisms, including DNA damage response, cell cycle regulation, cell death, inflammatory response, cancer stem cell and EGFR related pathways. This paper aimed to provide a summary of current findings on ncRNAs dysregulation after irradiation. We also present the function and mechanism of ncRNAs in modulating radiosensitivity or radioresistance of breast cancer cells.

Effects of repeated exposure to 50 Hz electromagnetic field on breast cancer cells.

The extremely low frequency electromagnetic field (ELF-EMF) is emerging as a novel approach in cancer treatment. This study evaluated the impact of daily exposure to 50 Hz EMF on breast cancer cells in vitro. The MDA-MB-231 and MCF-7 cells were exposed to EMF (50 Hz 20 mT, for 3 hours per day for up to four days) and examined for cell vaibility. The effect of daily ELF-EMF exposure on cell cycle progression and cell death was further investigated. The result revealed that the consecutive exposure to 50 Hz EMF at 20 mT remarkably decreased the viability of MDA-MB-231 compared to the non-exposed group, while it had no significant effect on MCF-7 cells. The ELF-EMF exposure induced G1 phase arrest along with the increase in sub-G1 cell population in MDA-MB-231. Moreover, repeated exposure to 50 Hz EMF promoted cell cycle progression in MCF-7 by increasing the percentage of cells in the S phase. The fluorescent staining revealed that daily exposure of ELF-EMF induced apoptotic cell death in MDA-MB-231, but no morphological change was observed in MCF-7 cells. The results showed that repeated daily exposure to 50 Hz EMF exhibited anti-proliferative activity against invasive breast cancer cells by impairing cell cycle progression and inducing cell death.

Inhibition of CDK4/6 as Therapeutic Approach for Ovarian Cancer Patients: Current Evidences and Future Perspectives.

Alterations in components of the cell-cycle machinery are present in essentially all tumor types. In particular, molecular alterations resulting in dysregulation of the G1 to S phase transition have been observed in almost all human tumors, including ovarian cancer. These alterations have been identified as potential therapeutic targets in several cancer types, thereby stimulating the development of small molecule inhibitors of the cyclin dependent kinases. Among these, CDK4 and CDK6 inhibitors confirmed in clinical trials that CDKs might indeed represent valid therapeutic targets in, at least some, types of cancer. CDK4 and CDK6 inhibitors are now used in clinic for the treatment of patients with estrogen receptor positive metastatic breast cancer and their clinical use is being tested in many other cancer types, alone or in combination with other agents. Here, we review the role of CDK4 and CDK6 complexes in ovarian cancer and propose the possible use of their inhibitors in the treatment of ovarian cancer patients with different types and stages of disease.

Differential miRNAs expression pattern of irradiated breast cancer cell lines is correlated with radiation sensitivity.

Radiotherapy is a fundamental step in the treatment of breast cancer patients. The treatment efficiency is however reduced by the possible onset of radiation resistance. In order to develop the effective treatment approach, it is important to understand molecular basis of radiosensitivity in breast cancer. The purpose of the present study was to investigate different radiation response of breast cancer cell lines, and find out if this response may be related to change in the microRNAs expression profile. MDA-MB-231 and T47D cells were subjected to different doses of radiation, then MTT and clonogenic assays were performed to assess radiation sensitivity. Cytofluorometric and western blot analysis were performed to gain insight into cell cycle distribution and protein expression. MicroRNA sequencing and bioinformatics prediction methods were used to identify the difference in microRNAs expression between two breast cancer cells and the related genes and pathways. T47D cells were more sensitive to radiation respect to MDA-MB-231 cells as demonstrated by a remarkable G2 cell cycle arrest followed by a greater reduction in cell viability and colony forming ability. Accordingly, T47D cells showed higher increase in the phosphorylation of ATM, TP53 and CDK1 (markers of radiation response) and faster and more pronounced increase in RAD51 and γH2AX expression (markers of DNA damage), when compared to MDA-MB-231 cells. The two cell lines had different microRNAs expression profiles with a confirmed significant differential expression of miR-16-5p, which targets cell cycle related genes and predicts longer overall survival of breast cancer patients, as determined by bioinformatics analysis. These results suggest a possible role for miR-16-5p as radiation sensitizing microRNA and as prognostic/predictive biomarker in breast cancer.

Enterolactone: A novel radiosensitizer for human breast cancer cell lines through impaired DNA repair and increased apoptosis.

INTRODUCTION: Radiotherapy is a potent treatment against breast cancer, which is the most commonly diagnosed cancer among women. However, the emergence of radioresistance due to increased DNA repair leads to radiotherapeutic failure. Applying polyphenols combined with radiation is a more promising method leading to better survival. Enterolactone, a phytoestrogenic polyphenol, has been reported to inhibit an important radioresistance signaling pathway, therefore we conjectured that enterolactone could enhance radiosensitivity in breast cancer. To assess this hypothesis, radiation response of enterolactone treated MDA-MB-231 and T47D cell lines and corresponding cellular mechanisms were investigated. METHODS: Cytotoxicity of enterolactone was measured via MTT assay. Cells were treated with enterolactone before X-irradiation, and clonogenic assay was used to evaluate radiosensitivity. Cell cycle distribution and apoptosis were measured by flow cytometric analysis. In addition, DNA damages and corresponding repair, chromosomal damages, and aberrations were assessed by comet, micronucleus, and cytogenetic assays, respectively. RESULTS: Enterolactone decreased the viability of cells in a concentration- and time dependent manner. Enterolactone significantly enhanced radiosensitivity of cells by abrogating G2/M arrest, impairing DNA repair, and increasing radiation-induced apoptosis. Furthermore, increased chromosomal damages and aberrations were detected in cells treated with enterolactone combined with X-rays than X-ray alone. These effects were more prominent in T47D than MDA-MB-231 cells. DISCUSSION: To our knowledge, this is the first report that enterolactone is a novel radiosensitizer for breast cancer irrespective of estrogen receptor status. Authors propose enterolactone as a candidate for combined therapy to decrease the radiation dose delivered to patients and subsequent side effects.