The role of endoplasmic reticulum stress in the regulation of long noncoding RNAs in cancer.

Cancer cells must overcome a variety of external and internal stresses to survive and proliferate. These unfavorable conditions include the accumulation of mutations, nutrient deficiency, oxidative stress, and hypoxia. These stresses can cause aggregation of misfolded proteins inside the endoplasmic reticulum. Under these conditions, the cell undergoes endoplasmic reticulum stress (ER-stress), and consequently initiates the unfolded protein response (UPR). Activation of the UPR triggers transcription factors and regulatory factors, including long noncoding RNAs (lncRNAs), which control the gene expression profile to maintain cellular stability and hemostasis. Recent investigations have shown that cancer cells can ensure their survival under adverse conditions by the UPR affecting the expression of lncRNAs. Therefore, understanding the relationship between lncRNA expression and ER stress could open new avenues, and suggest potential therapies to treat various types of cancer.

Combination therapy of mesenchymal stromal cells and sulfasalazine attenuates trinitrobenzene sulfonic acid induced colitis in the rat: The S1P pathway.

Adipose derived mesenchymal stem cells (ASCs) transplantation is a novel immunomodulatory therapeutic tool to ameliorate the symptom of inflammatory bowel disease (IBD). The objective of this study was to investigate the therapeutic effects of combined sufasalazine and ASCs therapy in a rat model of IBD. After induction of colitis in rats, ASCs were cultured and intraperitoneally injected (3 × 106 cells/kg) into the rats on Days 1 and 5 after inducing colitis, in conjunction with daily oral administration of low dose of sulfasalazine (30 mg/kg). The regenerative effects of combination of ASCs and sulfasalazine on ulcerative colitis were assessed by measuring body weight, colonic weight/length ratio, disease activity index, macroscopic scores, histopathological examinations, cytokine, and inflammation markers profiles. In addition, western blot analysis was used to assess the levels of nuclear factor-kappa B (NF-κB) and apoptosis related proteins in colitis tissues. Simultaneous treatment with ASCs and sulfasalazine was associated with significant amelioration of disease activity index, macroscopic and microscopic colitis scores, as well as inhibition of the proinflammatory cytokines in trinitrobenzene sulfonic acid (TNBS)-induced colitis. Moreover, combined ASCs and sulfasalazine therapy effectively inhibited the NF-κB signaling pathway, reduced the expression of Bax and prevented the loss of Bcl-2 proteins in colon tissue of the rats with TNBS-induced colitis. Furthermore, combined treatment with ASCs and sulfasalazine shifted inflammatory M1 to anti-inflammatory M2 macrophages by decreasing the levels of MCP1, CXCL9 and increasing IL-10, Arg-1 levels. In conclusion, combination of ASCs with conventional IBD therapy is potentially a much more powerful strategy to slow the progression of colitis via reducing inflammatory and apoptotic markers than either therapy alone.

Kaempferol-loaded bioactive glass-based scaffold for bone tissue engineering: in vitro and in vivo evaluation.

Due to the increasing prevalence of bone disorders among people especially in average age, the future of treatments for osseous abnormalities has been illuminated by scaffold-based bone tissue engineering. In this study, in vitro and in vivo properties of 58S bioactive glass-based scaffolds for bone tissue engineering (bare (B.SC), Zein-coated (C.SC), and Zein-coated containing Kaempferol (KC.SC)) were evaluated. This is a follow-up study on our previously published paper, where we synthesized 58S bioactive glass-based scaffolds coated with Kaempferol-loaded Zein biopolymer, and characterized from mostly engineering points of view to find the optimum composition. For this aim, in vitro assessments were done to evaluate the osteogenic capacity and biological features of the scaffolds. In the in vivo section, all types of scaffolds with/without bone marrow-derived stem cells (BMSC) were implanted into rat calvaria bone defects, and potential of bone healing was assessed using imaging, staining, and histomorphometric analyses. It was shown that, Zein-coating covered surface cracks leading to better mechanical properties without negative effect on bioactivity and cell attachment. Also, BMSC differentiation proved that the presence of Kaempferol caused higher calcium deposition, increased alkaline phosphatase activity, bone-specific gene upregulation in vitro. Further, in vivo study confirmed positive effect of BMSC-loaded KC.SC on significant new bone formation resulting in complete bone regeneration. Combining physical properties of coated scaffolds with the osteogenic effect of Kaempferol and BMSCs could represent a new strategy for bone regeneration and provide a more effective approach to repairing critical-sized bone defects.

Injectable hydrogels in central nervous system: Unique and novel platforms for promoting extracellular matrix remodeling and tissue engineering.

Repairing central nervous system (CNS) is difficult due to the inability of neurons to recover after damage. A clinically acceptable treatment to promote CNS functional recovery and regeneration is currently unavailable. According to recent studies, injectable hydrogels as biodegradable scaffolds for CNS tissue engineering and regeneration have exceptionally desirable attributes. Hydrogel has a biomimetic structure similar to extracellular matrix, hence has been considered a 3D scaffold for CNS regeneration. An interesting new type of hydrogel, injectable hydrogels, can be injected into target areas with little invasiveness and imitate several aspects of CNS. Injectable hydrogels are being researched as therapeutic agents because they may imitate numerous properties of CNS tissues and hence reduce subsequent injury and regenerate neural tissue. Because of their less adverse effects and cost, easier use and implantation with less pain, and faster regeneration capacity, injectable hydrogels, are more desirable than non-injectable hydrogels. This article discusses the pathophysiology of CNS and the use of several kinds of injectable hydrogels for brain and spinal cord tissue engineering, paying particular emphasis to recent experimental studies.

Tissue-Engineered Core-Shell Silk-Fibroin/Poly-l-Lactic Acid Nerve Guidance Conduit Containing Encapsulated Exosomes of Human Endometrial Stem Cells Promotes Peripheral Nerve Regeneration.

Nerve guide conduits (NGCs) have been shown to be less efficient than nerve autografts in peripheral nerve regeneration. To address this issue, we developed for the first time a novel tissue-engineered nerve guide conduit structure encapsulated with human endometrial stem cell (EnSC) derived exosomes, which promoted nerve regeneration in rat sciatic nerve defects. In this study, we initially indicated the long-term efficacy and safety impacts of newly designed double layered SF/PLLA nerve guide conduits. Then the regeneration effects of SF/PLLA nerve guide conduits containing exosomes derived from human EnSCs were evaluated in rat sciatic nerve defects. The human EnSC derived exosomes were isolated from the supernatant of human EnSC cultures and characterized. Subsequently, the human EnSC derived exosomes were encapsulated in constructed NGCs by fibrin gel. For in vivo studies, entire 10 mm peripheral nerve defects were generated in rat sciatic nerves and restored with NGC encapsulated with human EnSC derived exosomes (Exo-NGC group), nerve guide conduits, and autografts. The efficiency of the NGCs encapsulated with human EnSCs derived exosomes in assisting peripheral nerve regeneration was investigated and compared with other groups. The in vivo results demonstrated that encapsulated human EnSC derived exosomes in NGC (Exo-NGC) significantly benefitted nerve regeneration based on motor function, sensory reaction, and electrophysiological results. Furthermore, immunohistochemistry with histopathology results showed the formation of regenerated nerve fibers, along with blood vessels that newly were developed, as a result of the exosome functions in the Exo-NGC group. These outcomes illustrated that the newly designed core-shell SF/PLLA nerve guide conduit encapsulated with human EnSC derived exosomes enhanced the regeneration process of axons and improved the functional recovery of rat sciatic nerve defects. So, encapsulated human EnSC-derived exosomes in a core-shell SF/PLLA nerve guide conduit are a potential therapeutic cell-free treatment for peripheral nerve defects.

Bridging potential of Taurine-loading PCL conduits transplanted with hEnSCs on resected sciatic nerves.

Reconstruction of nerve conduits is a promising method for functional improvement in peripheral nerve repair. Besides choosing of a suitable polymer for conduit construction, adding factors such as Taurine improve a more advantageous microenvironment for defect nerve regeneration. Showing several major biological properties of Taurine, for example, regulation of the osmotic pressure, modulation of neurogenesis, and calcium hemostasis, makes it an appropriate option for repairing of defected nerves. To this, we examined repairing effects of Taurine-loading PCL conduits cultured with human endothelial stem cells (hEnSCs) on resected sciatic nerves. PCL/Taurine/Cell conduits transplanted to a 10-mm sciatic nerve gap. Forty-two wistar rats were randomly divided to seven groups: (1) Normal group, (2) Negative control (NC), (3) Positive control (nerve Autograft group), (4) PCL conduits group (PCL), (5) Taurine loaded PCL conduits group (PCL/Taurine), (6) hEnSCs cultured on the PCL conduits (PCL/Cell), (7) hEnSCs cultured on the PCL/Taurine conduits (PCL/Taurine/Cell). Functional recovery of motor and sensory nerves, the action potential of exciting muscle and motor distal latency has seen in PCL/Taurine/Cell conduits. Histological studies showed also remarkable nerve regeneration and obvious bridging has seen in this group. In conclusion, PCL/Taurine/Cell conduits showing suitable mechanical properties and biocompatibility may improve sciatic nerve regeneration.

Advanced approaches to regenerate spinal cord injury: The development of cell and tissue engineering therapy and combinational treatments.

Spinal cord injury (SCI) is a central nervous system (CNS) devastate event that is commonly caused by traumatic or non-traumatic events. The reinnervation of spinal cord axons is hampered through a myriad of devices counting on the damaged myelin, inflammation, glial scar, and defective inhibitory molecules. Unfortunately, an effective treatment to completely repair SCI and improve functional recovery has not been found. In this regard, strategies such as using cells, biomaterials, biomolecules, and drugs have been reported to be effective for SCI recovery. Furthermore, recent advances in combinatorial treatments, which address various aspects of SCI pathophysiology, provide optimistic outcomes for spinal cord regeneration. According to the global importance of SCI, the goal of this article review is to provide an overview of the pathophysiology of SCI, with an emphasis on the latest modes of intervention and current advanced approaches for the treatment of SCI, in conjunction with an assessment of combinatorial approaches in preclinical and clinical trials. So, this article can give scientists and clinicians' clues to help them better understand how to construct preclinical and clinical studies that could lead to a breakthrough in spinal cord regeneration.

Tissue-engineered nerve graft using silk-fibroin/polycaprolactone fibrous mats decorated with bioactive cerium oxide nanoparticles.

The main aim of this study was to evaluate the efficacy of cerium oxide nanoparticles (CNPs) encapsulated in fabricated hybrid silk-fibroin (SF)/polycaprolactone (PCL) nanofibers as an artificial neural guidance conduit (NGC) applicable for peripheral nerve regeneration. The NGC was prepared by PCL and SF filled with CNPs. The mechanical properties, contact angle, and cell biocompatibility experiments showed that the optimized concentration of CNPs inside SF and SF/PCL wall of conduits was 1% (wt/wt). The SEM image analysis showed the nanoscale texture of the scaffold in different topologies depend on composition with fiber diameters at about 351 ± 54 nm and 420 ± 73 nm respectively for CNPs + SF and CNPs + SF/PCL fibrous mats. Furthermore, contact angle measurement confirmed the hydrophilic behavior of the membranes, ascribable to the SF content and surface modification through modified methanol treatment. The balance of morphological and biochemical properties of hybrid CNPs 1% (wt/wt) + SF/PCL construct improves cell adhesion and proliferation in comparison with lower concentrations of CNPs in nanofibrous scaffolds. The release of CNPs 1% (wt/wt) from both CNPs + SF and CNPs+ SF/PCL fibrous mats was highly controlled and very slow during the extended time of incubation until 60 days. Fabricated double-layered NGC using CNPs + SF and CNPs + SF/PCL fibers was consistent for application in nervous tissue engineering and regenerative medicine from a structural and biocompatible perspective.

Fabrication of chitosan-polyvinyl alcohol and silk electrospun fiber seeded with differentiated keratinocyte for skin tissue regeneration in animal wound model.

Hybrid fibrous mat containing cell interactive molecules offers the ability to deliver the cells and drugs in wound bed, which will help to achieve a high therapeutic treatment. In this study, a co-electrospun hybrid of polyvinyl alcohol (PVA), chitosan (Ch) and silk fibrous mat was developed and their wound healing potential by localizing bone marrow mesenchymal stem cells (MSCs)-derived keratinocytes on it was evaluated in vitro and in vivo. It was expected that fabricated hybrid construct could promote wound healing due to its structure, physical, biological specifications. The fabricated fibrous mats were characterized for their structural, mechanical and biochemical properties. The shape uniformity and pore size of fibers showed smooth and homogenous structures of them. Fourier transform infrared spectroscopy (FTIR) verified all typical absorption characteristics of Ch-PVA + Silk polymers as well as Ch-PVA or pure PVA substrates. The contact angle and wettability measurement of fibers showed that mats found moderate hydrophilicity by addition of Ch and silk substrates compared with PVA alone. The mechanical features of Ch-PVA + Silk fibrous mat increase significantly through co-electrospun process as well as hybridization of these synthetic and natural polymers. Higher degrees of cellular attachment and proliferation obtained on Ch-PVA + Silk fibers compared with PVA and Ch-PVA fibers. In terms of the capability of Ch-PVA + Silk fibers and MSC-derived keratinocytes, histological analysis and skin regeneration results showed this novel fibrous construct could be suggested as a skin substitute in the repair of injured skin and regenerative medicine applications.

Focal adhesion kinase (FAK) involvement in human endometrial remodeling during the menstrual cycle.

BACKGROUND: Endometrial remodeling occurs during each menstrual cycle in women. Reports have shown that, in a variety of cell types, processes such as proliferation, signaling complex formation and extra cellular matrix remodeling require a cytoplasmic tyrosine kinase, focal adhesion kinase (FAK). The present study has focused on the expression pattern of FAK in human endometrium during the menstrual cycle. The purpose of this study was to ascertain the probable function of FAK in menstrual cycle changes and the role of FAK in tissue repair and tissue remodeling in vivo. METHODS: Formalin-fixed paraffin-embedded endometrial samples were obtained from 400 pre-menopausal, non-pregnant women, who underwent hysterectomy and biopsy for benign diseases. Forty six samples with no tissue abnormalities were studied and ABC staining method of immuno-histochemistry methods was applied. Positive staining of FAK by different cell types of human endometrium was scaled and compared with each other by using histologic score method. RESULTS: All different cell types of endometrium showed various patterns of FAK expression in different stages of menstruation. FAK in glandular and luminal epithelial cells is up-regulated during the early proliferative (EP) to mid-secretory (MS) phases. FAK in stromal cells is up-regulated during the EP, early and MS phases in comparison to the late secretory (LS) phase. FAK expression in endothelial cells is up-regulated during the EP and MS phases in comparison to LS phase. This study showed that endometrial FAK expression is a phase-dependent manner during the menstrual cycle. CONCLUSION: It appears that up-regulation of FAK during the proliferative phases is responsible for endometrial regeneration and high expression of FAK in the EP and MS phases may associate with the implantation. Down-regulation of FAK during the LS phase may facilitate apoptosis in human endometrium. It seems that FAK as a key kinase plays a critical role in endometrial remodeling that it may regulate by steroid hormones.

Effect of Polygonum Aviculare L. on Nephrolithiasis Induced by Ethylene Glycol and Ammonium Chloride in Rats.

PURPOSE: Nephrolithiasis is a common urinary tract disease, in addition to the pain and treatment costs, there may be significant complications resulting from the stones. This study intended to investigate the effects of Polygonum Aviculare L. aqueous extract (PAE) on urolithiasis induced by ethylene glycol (EG) and ammonium chloride (AC) in rats. MATERIALS AND METHODS: Sixty-four male Wistar rats were randomly divided into eight groups (n = 8). Rats in the normal control group (I) received no treatment. The sham groups (III and IV) were given PAE. at 100 and400 mg/kg by gavage for 28 days. The disease control group (II), the prevention groups ( V and VI), and the therapeutic groups (VII and VIII), received 1% EG and .25 AC in their drinking water for 28 days. The prevention groups (from the start of EG administration), and the therapeutic groups (from the 14th day of EG administration),received PAE at 100 and 400 mg/kg by gavage. At the end of the experiment, kidneys were examined for CaOx deposits and tubulointerstitial changes. RESULTS: The number of CaOx crystals and tubulointerstitial changes increased significantly in group II rats compared to groups I, III, and IV (P < .001). The number of CaOx crystals (P < .001) and tubulointerstitial changes (P < .001) in the prevention groups, and the number of CaOx crystals (P < .05) and interstitial changes (P < .05) inthe therapeutic groups declined significantly compared to group II. CONCLUSION: Results show aqueous extract of Polygonum Aviculare L. is effective in the prevention and treatment of kidney stones.

Effect of Malva Neglecta Wallr on Ethylene Glycol Induced Kidney Stones.

PURPOSE: The aim of this study was to investigate the anti-urolithiasis effects of aqueous extracts of Malva neglecta Wallr on ethylene glycol and ammonium chloride induced kidney stones in a rat model. MATERIALS AND METHODS: A total number of 64 male Wistar rats were randomly divided into eight groups equally: group I (normal control), group II (disease control), groups III and IV (sham), groups V and VI (preventive groups), and groups VII and VIII (curative groups). Group I received tap drinking water, groups III and IV were given intra-peritoneal injections of 200 and 800 mg/kg aqueous extracts for 28 days. Groups II, V, VI, VII, and VIII received 1% ethylene glycol plus 0.25% ammonium chloride in drinking water for 28 days. Groups V and VI were given intra- peritoneal injections of 200 and 800 mg/kg aqueous extracts for 28 days and groups VII and VIII received intra-peritoneal injections of 200 and 800 mg/kg aqueous extracts from the 14th day of the experiment. After 28 days the kidneys were removed and observed for calcium oxalate (CaOx) deposits and tubulointerstitial changes. RESULTS: The extract significantly decreased CaOx deposits and tubulointerstitial damage in the preventive groups (P < .001). In curative groups, a low dosage of extract, reduced kidney oxalate deposits and tubulointerstitial damage (P < .05). In addition a significant decrease was observed in crystal deposition and tubulointerstitial damage in high dosed group (P < .001). However, high dosed preventive and curative groups seemed to be more effective (P ≤ .001). CONCLUSION: Malva neglecta Wallr has beneficial effects on preventing and treating CaOx deposition and decreasing tubulointerstitial damage on a dosage dependent manner. These effects may be due to the components presented in this plant such as saponins, flavonoids, mucilage, and phenolic compounds.