Small nucleolar RNA host genes promoting epithelial-mesenchymal transition lead cancer progression and metastasis.

The small nucleolar RNA host genes (SNHGs) belong to the long non-coding RNAs and are reported to be able to influence all three levels of cellular information-bearing molecules, that is, DNA, RNA, and proteins, resulting in the generation of complex phenomena. As the host genes of the small nucleolar RNAs (snoRNAs), they are commonly localized in the nucleolus, where they exert multiple regulatory functions orchestrating cellular homeostasis and differentiation as well as metastasis and chemoresistance. Indeed, worldwide literature has reported their involvement in the epithelial-mesenchymal transition (EMT) of different histotypes of cancer, being able to exploit peculiar features, for example, the possibility to act both in the nucleus and the cytoplasm. Moreover, SNHGs regulation is a fundamental topic to better understand their role in tumor progression albeit such mechanism is still debated. Here, we reviewed the biological functions of SNHGs in particular in the EMT process and discussed the perspectives for new cancer therapies.

Paving the Road Toward Exploiting the Therapeutic Effects of Ginsenosides: An Emphasis on Autophagy and Endoplasmic Reticulum Stress.

Programmed cell death processes such as apoptosis and autophagy strongly contribute to the onset and progression of cancer. Along with these lines, modulation of cell death mechanisms to combat cancer cells and elimination of resistance to apoptosis is of great interest. It appears that modulation of autophagy and endoplasmic reticulum (ER) stress with specific agents would be beneficial in the treatment of several disorders. Interestingly, it has been suggested that herbal natural products may be suitable candidates for the modulation of these processes due to few side effects and significant therapeutic potential. Ginsenosides are derivatives of ginseng and exert modulatory effects on the molecular mechanisms associated with autophagy and ER stress. Ginsenosides act as smart phytochemicals that confer their effects by up-regulating ATG proteins and converting LC3-I to -II, which results in maturation of autophagosomes. Not only do ginsenosides promote autophagy but they also possess protective and therapeutic properties due to their capacity to modulate ER stress and up- and down-regulate and/or dephosphorylate UPR transducers such as IRE1, PERK, and ATF6. Thus, it would appear that ginsenosides are promising agents to potentially restore tissue malfunction and possibly eliminate cancer.

The particle size of drug nanocarriers dictates the fate of neurons; critical points in neurological therapeutics.

Neurological disorders and diseases are on the rise in the world, while pharmacists are being encouraged to encapsulate drugs into the nanocarriers. The critical key question is which size of nanocarrier has a promising neurotherapeutic effect. In the present study, FTY-720, an FDA approved drug, was encapsulated into O/W nanocarriers. SEM and DLS data indicated in ultrasonication and stirring methods resulted in spherical nanocarriers with a particle size of 60 and 195 nm (nF60 and nF195), respectively. Further to investigate the effect of particle size on neuronal cells, MTT assay, PI flow-cytometry, LDH release, and NO production examinations were performed. Results showed that small nanocarriers increased cell viability along with the decline of dead cells, while both nanocarriers decreased LDH release and NO production as compared to the conventional drug. Notably, qRT-PCR and western blotting data related to apoptotic markers indicated in the increase of cell mortality in cells treated by nF190 was not due to the increase of apoptosis and Bax/Bcl2 ratio. It is worth mentioning that integrin α5 as a cell surface receptor involves in neuritogenesis was over-expressed in neuronal cells treated by small nanocarriers. However, nF60 increased PTK2 over-expression along with neurite outgrowth, as well. In other words, nanocarriers at the size of 60 nm are preferred to 195 nm as a drug carrier in neurotherapy due to profound impacts on neural cells. Thanks to small nanocarrier broad positive action on neural viability and neurite outgrowth. The present study discloses a pharmaceutical strategy to design drugs based on their particle size efficiency.

Therapeutic effects of kaempferol affecting autophagy and endoplasmic reticulum stress.

Regulated cell death (RCD) guarantees to preserve organismal homeostasis. Apoptosis and autophagy are two major arms of RCD, while endoplasmic reticulum (ER) as a crucial organelle involved in proteostasis, promotes cells toward autophagy and apoptosis. Alteration in ER stress and autophagy machinery is responsible for a great number of diseases. Therefore, targeting those pathways appears to be beneficial in the treatment of relevant diseases. Meantime, among the traditional herb medicine, kaempferol as a flavonoid seems to be promising to modulate ER stress and autophagy and exhibits protective effects on malfunctioning cells. There are some reports indicating the capability of kaempferol in affecting autophagy and ER stress. In brief, kaempferol modulates autophagy in noncancerous cells to protect cells against malfunction, while it induces cell mortality derived from autophagy through the elevation of p-AMP-activated protein kinase, light chain-3-II, autophagy-related geness, and Beclin-1 in cancer cells. Noteworthy, kaempferol enhances cell survival through C/EBP homologous protein (CHOP) suppression and GRP78 increment in noncancerous cells, while it enhances cell mortality through the induction of unfolding protein response and CHOP increment in cancer cells. In this review, we discuss how kaempferol modulates autophagy and ER stress in noncancer and cancer cells to expand our knowledge of new pharmacological compounds for the treatment of associated diseases.

Curcumin Delivery Mediated by Bio-Based Nanoparticles: A Review.

Todays, nano-pharmaceutics is emerging as an important field of science to develop and improve efficacy of different drugs. Although nutraceuticals are currently being utilized in the prevention and treatment of various chronic diseases such as cancers, a number of them have displayed issues associated with their solubility, bioavailability, and bio-degradability. In the present review, we focus on curcumin, an important and widely used polyphenol, with diverse pharmacological activities such as anti-inflammatory, anti-carcinogenic, anti-viral, etc. Notwithstanding, it also exhibits poor solubility and bioavailability that may compromise its clinical application to a great extent. Therefore, the manipulation and encapsulation of curcumin into a nanocarrier formulation can overcome these major drawbacks and potentially may lead to a far superior therapeutic efficacy. Among different types of nanocarriers, biological and biopolymer carriers have attracted a significant attention due to their pleiotropic features. Thus, in the present review, the potential protective and therapeutic applications of curcumin, as well as different types of bio-nanocarriers, which can be used to deliver curcumin effectively to the different target sites will be discussed.

Acidic pH derived from cancer cells as a double-edged knife modulates wound healing through DNA repair genes and autophagy.

Wound healing is a sequester program that involves diverse cell signalling cascades. Notwithstanding, complete signal transduction pathways underpinning acidic milieu derived from cancer cells is not clear, yet. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, fluorescein diacetate/propidium iodide staining, and cell cycle flow cytometry revealed that acidic media decreased cell viability and cell number along with enhanced dead cells and S-phase arrest in normal fibroblasts. Notably, the trends of intracellular reactive oxygen species production and lactate dehydrogenase release significantly increased with time. It seems the downregulation of Klf4 is in part due to acidosis-induced DNA damage. It promoted cells towards S-phase arrest and diminished cell proliferation. Klf4 downregulation had a direct correlation with the P53 level while acidic microenvironment promotes cells towards cell death mechanisms including apoptosis and autophagy. Noteworthily, the unchanged levels of Rb and Mlh1 indicated in those genes had no dominant role in the repairing of DNA damage in fibroblasts treated with the acidic microenvironment. Therefore, cells owing to not entering to mitosis and accumulation of DNA damage were undergone cell death to preserve cell homeostasis. Since acidic media decreased the level of tumour suppressor and DNA repair genes and altered the normal survival pathways in fibroblasts, caution should be exercised to not lead to cancer rather than wound healing.

Therapeutic potential of human mesenchymal stem cells derived beta cell precursors on a nanofibrous scaffold: An approach to treat diabetes mellitus.

Diabetes mellitus is an autoimmune and chronic disorder that is rapidly expanding worldwide due to increasing obesity. In the current study, we were able to design a reliable 3-dimensional differentiation process of human Wharton's jelly mesenchymal stem cells into pancreatic beta cell precursors (PBCPs) and detected that transplanted PBCPs could improve hyperglycemia in a diabetes-induced model in mice. Polylactic acid/chitosan nanofibrous scaffold was prepared using an electrospinning method. Quantitative real-time reverse transcription-polymerase chain reaction and immunocytochemistry analysis were carried out to assess pancreatic marker expression in the differentiated cells. PBCPs were transplanted under the kidney capsule of diabetic mice that induced streptozotocin injection 14 days before the transplantation. Moreover, an intraperitoneal glucose tolerance test (ipGTT) was carried out 2 and 4 weeks after the transplantation to measure the reaction to a sudden increase of the blood glucose level in the transplanted animals. The results indicated that the expression of SRY (sex determining region Y)-box (Sox17), forkhead box A2 (FoxA2), pancreatic and duodenal homeobox 1 (Pdx1), neurogenin 3 (Ngn3), hepatic nuclear factor 4, alpha (Hnf4α), and NK2 homeobox 2 (Nkx2.2) were increased significantly in the differentiated cells compared with that of the control group. In the current study, the diabetic disease was confirmed by measuring blood glucose and proved by conducting some other behavioral tests. After the PBCPs transplantation in a diabetic model, the ipGTT and hyperglycemia investigation during the determinant times confirmed the disease's significant improvement in the experimental models. In this study, some preclinical data suggested that the transplantation of PBCPs associated with appropriate nanofiber scaffold can be utilized for the treatment of diabetes models. In addition, studies are required to elucidate the molecular mechanism of PBCPs acting in diabetes models before being used for patients with diabetes.

Autophagy, anoikis, ferroptosis, necroptosis, and endoplasmic reticulum stress: Potential applications in melanoma therapy.

Melanoma as the most major skin malignancy has attracted much attention, so far. Although a successful therapeutic strategy requires an accurate understanding of the precise mechanisms for the initiation and progression of the melanoma. Several types of cell death mechanisms have recently been identified along with conventional cell death mechanisms such as apoptosis and necrosis. Among those mechanisms, necroptosis, anoikis, ferroptosis, and autophagy may be considered to have remarkable modulatory impacts on melanoma. In the present review, we explain the mechanisms of cell death signaling pathways related to autophagy, ferroptosis, anoikis, necroptosis, and reticulum endoplasmic stress in cells and describe how those mechanisms transduce signals in melanoma cells. Meanwhile, we describe how we can modulate those mechanisms to eliminate melanoma.

Berberine as a potential autophagy modulator.

Today, pharmacognosy is considered a valuable science in the prevention and treatment of diseases. Among herbals, Berberine is an isoquinoline alkaloid found in the Berberis species. Surprisingly, it shows antimicrobial, antiviral, antidiarrheal, antipyretic, and anti-inflammatory potential. Furthermore, it diminishes drug resistance in cancer therapy and enhances tumor suppression in part through autophagy and cell cycle arrest mechanisms. In the present review, we discuss the effect of berberine on diverse cellular pathways and describe how berberine acts as an autophagy modulator to adjust physiologic and pathologic conditions and diminishes drug resistance in cancer therapy.

Autophagic, apoptotic, and necrotic cancer cell fates triggered by acidic pH microenvironment.

Cancer as a multifactorial and smart disease is now considered a challenging problem. Despite many investigations on drug discovery, it remains incurable, in part, due to insufficient understanding of its special mechanisms. For the first time, we collaterally investigated the effect of acidosis on the contribution of apoptosis, necrosis, and autophagy in MDA-MB 231 cells. Our data showed that necrosis, apoptosis, and intracellular reactive oxygen species production drastically decreased from 48 to 72 hr while cell viability and autophagy increased along with a gap between the percentages. Eventually, the decrease of necrosis and apoptosis was related to upregulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and fatty acid synthetase, respectively. It seems that at the early stage of cancer progression, apoptosis is the main mechanism of cell mortality and afterward autophagy would be the main mechanism of cell survival. Therefore, at the acute phase of cancer, apoptotic inducer medications would be effective while at the chronic phase of cancer progression, autophagy inhibitor medication would be added as well. This eventually means that autophagy acts as both cell death and survival mechanisms at the onset of cancer progression with the approach towards cell survival. Besides other unknown cell survival mechanisms are involved in cell viability, except for apoptosis and necrosis inhibition and autophagy improvement. This study reiterates the inefficaciousness of autophagy inhibitor's medication at the onset of disease. It also emphasizes discovering other cell death mechanisms for cancer cell adaptation at the onset of disease with the aim of their targeting in cancer invasion therapy.

Strong binding active constituents of phytochemical to BMPR1A promote bone regeneration: In vitro, in silico docking, and in vivo studies.

Two of the most problematic orthopedic and neurosurgeon visits are associated with spine and craniofacial fractures. Therefore, more attention needs to be paid to finding a medicine to repair these fractures. Amongst the most mysterious herbs, Aloe vera stands out. In the present study, the ameliorating function of A. vera on osteogenesis was studied in vitro and in vivo. Osteoblast-like cells were exposed to A. vera, followed by analysis of cell viability, lactate dehydrogenase release, and intracellular reactive oxygen species (ROS) production. The results showed an enhanced cell biocompatibility in a dose-dependent manner due to attenuated intracellular ROS production. Furthermore, a docking study indicated that the strong affinity of A. vera constituents to type I bone morphogenic protein receptor (BMPR1A) without the involvement of the BMPR1A chain B. The induction of osteogenesis prompts extracellular calcium deposition by osteoblasts, which affirms successful in vitro bone regeneration. However, injection of A. vera in rats with critical size calvarial defects induced Runx2, alkaline phosphatase (ALP), OCN, and BMP2 genes overexpression, which led to the formation of victorious bone with enhanced bone density and ALP activity. It is worthy to note that Aloin has the highest affinity to BMPR1A, whereas there are no reports regarding the impact of Aloenin, Aloesin, and γ-sitosterol on osteogenesis. Furthermore, some of them have antitumor potency, and it might be proposed that they are considered as a bone substitute in the osteotomy site of osteosarcoma with the aim of bone recovery and suppression of osteosarcoma. The whole consequences of this investigation manifests the plausibility of using A. vera as an antioxidant and osteoconductive substitute.

Small molecule of sphingosine as a rescue of dopaminergic cells: A cell therapy approach in neurodegenerative diseases therapeutics.

Multiple sclerosis (MS) patients should take medication such as fingolimod (FTY-720) for a long time, hence pharmaceutical effects on other neural cells such as dopaminergic cells are important. Dopaminergic cell line, BE(2)-M17, was treated by FTY-720 and then cell viability and genes involve in neurosurvival were investigated. It was disclosed that FTY-720 significantly stimulates Bcl2 overexpression. Whereas, it decreased intracellular reactive oxygen species production and cell membrane damage of dopaminergic cells. The increase in Bcl2/Bax ratio increased the cell metabolic activity and decreased propidium iodide-positive cells. Besides, FTY-720 induced the overexpression of CACNA1C, nNOS gene, and nitric oxide production. However, FTY-720 induced GABARA1 overexpression and eventually it could overcame to the cytotoxic effect of intracellular calcium. This cascade led to tyrosine hydroxylase and BDNF genes overexpression whereas FTY-720 did not change GDNF concentration in BE(2)-M17 cells. Concluding, it might be said that taking FTY-720 in MS patients did not induce adverse effect on dopaminergic cells.

A combination therapy of nanoethosomal piroxicam formulation along with iontophoresis as an anti-inflammatory transdermal delivery system for wound healing.

Inflammation accounts as one of the major phases in wound healing, while prolonged and chronic inflammation may lead to adverse pathological conditions. Therefore, transdermal delivery of nonsteroidal anti-inflammatory (NSAIDs) such as encapsulated piroxicam into a nanocarrier seems to be promising. For the first time, a nanoethosomal piroxicam of <200 nm was prepared and combined with iontophoresis. Results showed that there was a critical point at the concentration of 5 mg lecithin with the smallest particle size. Besides, lecithin concentration had direct and inverse linear relationships with turbidity and pH of nanocarriers, respectively. Moreover, as there was no linear relationship between the lecithin concentration and particle size, the effect of lecithin concentration was dominant on turbidity compared with particle size. It seems that a pH higher than 5.5 disturbed the linear relationship of pH and entrapment efficacy percentage (EE%) while at the pH range of 4 to 5.5, the relationship was linear and EE% gradually decreased with increasing pH. These data showed that an optimised nanocarrier with special physicochemical properties is dominant to the just particle size. Besides, ex vivo permeation studies in rat skin showed that there was no significant difference between the permeation of free drug and ethosomal ones. However, iontophoresis significantly enhanced ethosomal piroxicam permeation compared with the free drug. Overall, these data emphasise the superiority of iontophoresis for the transdermal delivery of nanoethosomal medications while nanoethosomal delivery without iontophoresis did not show significant transdermal potential. To sum up, transdermal nanoethosomal piroxicam along with iontophoresis seems to be promising in wound healing.

Differential effect of Activin A and WNT3a on definitive endoderm differentiation on electrospun nanofibrous PCL scaffold.

The first step in the formation of hepatocytes and beta cells is the generation of definitive endoderm (DE) which involves a central issue in developmental biology. Human induced pluripotent stem cells (hiPSCs) have the pluripotency to differentiate into all three germ layers in vitro and have been considered potent candidates for regenerative medicine as an unlimited source of cells for therapeutic applications. In this study, we investigated the differentiating potential of hiPSCs on poly (ε-caprolactone) (PCL) nanofibrous scaffold into DE cells. Here, we demonstrate directed differentiation of hiPSCs by factors such as Activin A and Wnt3a. The differentiation was determined by immunofluoresence staining with Sox17, FoxA2 and Goosecoid (Gsc) and also by qRT-PCR analysis. The results of this study showed that hiPSCs, as a new cell source, have the ability to differentiate into DE cells with a high capacity and also demonstrate that three dimension (3D) culture provides a suitable nanoenviroment for growth, proliferation and differentiation of hiPSCs. PCL nanofibrous scaffold with essential supplements, stimulating factors and EB-derived cells is able to provide a novel method for enhancing functional differentiation of hiPSCs into DE cells.

Functionalisation and surface modification of electrospun polylactic acid scaffold for tissue engineering.

Repair or replacement of damaged tissues using tissue engineering technology is considered to be a fine solution for enhanced treatment of different diseases such as skin diseases. Although the nanofibers made of synthetic degradable polymers, such as polylactic acid (PLA), have been widely used in the medical field, they do not favour cellular adhesion and proliferation. To enhance cell adherence on scaffold and improve biocompatibility, the surface of PLA scaffold was modified by gelatin in our experiments. For electrospinning, PLA and gelatin were dissolved in hexafluoroisopropanol (HFIP) solvent at varying compositions (PLA:gelatin at 3:7 and 7:3). The properties of the blending nanofiber scaffold were investigated by Fourier transform infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM). Modified PLA/gelatin 7/3 scaffold is more suitable for fibroblasts attachment and viability than the PLA or gelatin nanofiber alone. Thus fibroblast cultured on PLA/gelatin scaffold could be an alternative way to improve skin wound healing.

Unraveling Dysregulated Cell Signaling Pathways, Genetic and Epigenetic Mysteries of Parkinson's Disease.

Parkinson's disease (PD) is a prevalent and burdensome neurodegenerative disorder that has been extensively researched to understand its complex etiology, diagnosis, and treatment. The interplay between genetic and environmental factors in PD makes its pathophysiology difficult to comprehend, emphasizing the need for further investigation into genetic and epigenetic markers involved in the disease. Early diagnosis is crucial for optimal management of the disease, and the development of novel diagnostic biomarkers is ongoing. Although many efforts have been made in the field of recognition and interpretation of the mechanisms involved in the pathophysiology of the disease, the current knowledge about PD is just the tip of the iceberg. By scrutinizing genetic and epigenetic patterns underlying PD, new avenues can be opened for dissecting the pathology of the disorder, leading to more precise and efficient diagnostic and therapeutic approaches. This review emphasizes the importance of studying dysregulated cell signaling pathways and molecular processes associated with genes and epigenetic alterations in understanding PD, paving the way for the development of novel therapeutic strategies to combat this devastating disease.

Effect of laminated hydroxyapatite/gelatin nanocomposite scaffold structure on osteogenesis using unrestricted somatic stem cells in rat.

Bone matrix consists of two major phases at the nanoscale: organic and hydroxyapatite. Nanotechnology as a diverse and interdisciplinary area of research has the capacity to revolutionise many areas of applications such as bone tissue engineering. Nanohydroxyapatite/gelatin composite has higher osteoblast attachment and proliferation than micro-sized ones, and shorter culturing period and lower cell seeding density compared to pure gelatin. A nanostructured scaffold was fabricated by three methods for bone repair using nanohydroxyapatite and gelatin as the main components. Its biocompatibility, alizarin red test on the 14th and 21st days, gene expression on the 21st day in in vitro using and histomorphometry after 4 and 8 weeks post-implantation in the rat were investigated. Cultured unrestricted somatic stem cells used for in vitro study showed an excellent level of cell attachment to the scaffold. Cells induced more osteoblast differentiation on the scaffold than in 2D cell culture. Osteoblast differentiation and bone regeneration results of in vitro and in vivo investigation on scaffold were extremely significant, better than control and treatment groups. These effects could be attributed to the shape and size of nanoHA particles and good architecture of the scaffold. The results confirm the feasibility of bone regeneration using synthesised scaffold as a temporary bone substitute.

The effect of carrier type on bone regeneration of demineralized bone matrix in vivo.

Demineralized bone matrix (DBM) is a bone substitute biomaterial used as an excellent grafting material. Some factors such as carrier type might affect the healing potential of this material. The background data discuss the present status of the field: Albumin as a main protein in blood and carboxymethyl cellulose (CMC) were applied frequently in the DBM gels. We investigated the bone-repairing properties of 2 DBMs with different carriers. Bone regeneration in 3 groups of rat calvaria treated with DBM from the Iranian Tissue Bank Research and Preparation Center, DBM from Hans Biomed Corporation, and an empty cavity was studied. Albumin and CMC as carriers were used. The results of bone regeneration in the samples after 1, 4, and 8 weeks of implantation were compared. The block of the histologic samples was stained with hematoxylin and eosin, and the percentage area of bone formation was calculated using the histomorphometry method. The results of in vivo tests showed a significantly stronger new regenerated bone occupation in the DBM with albumin carrier compared with the one with CMC 8 weeks after the implantation. The 2 types of DBM had a significant difference in bone regeneration. This difference is attributed to the type of carriers. Albumin could improve mineralization and bioactivity compared with CMC.

Cancer cells same as zombies reprogram normal cells via the secreted microenvironment.

The cancer microenvironment plays a crucial role in promoting metastasis and malignancy even in normal cells. In the present study, the effect of acidic and conditioned media of cancer cells (MDA-MB-231), separately and in combination, was studied for the first time on the cell death mechanisms and DNA methylation of normal fibroblasts (NIH/3T3). Cell survival of conditioned media was rescued by the addition of acidic media to conditioned media, as shown by the results. Cell metabolic activity is deviated in a direction other than the Krebs cycle by acidic media The mitochondrial metabolic activity of all groups was enhanced over time, except for acidic media. Unlike the highest amount of ROS in conditioned media, its level decreased to the level of acidic media in the combination group. Furthermore, cells were deviated towards autophagy, rather than apoptosis, by the addition of acidic media to the conditioned media, unlike the conditioned media. Global DNA methylation analysis revealed significantly higher DNA hypomethylation in acidic media than in normal and combination media. Not only were cells treated with conditioned media rescued by acidic media, but also DNA hypomethylation and apoptosis in the combination group were decreased through epigenetic modifications. The acidic and conditioned media produced by cancer cells can remotely activate malignant signaling pathways, much like zombies, which can cause metabolic and epigenetic changes in normal cells.