The interactome of cystic fibrosis transmembrane conductance regulator and its role in male fertility: A critical review.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic adenosine monophosphate (cAMP)-regulated chloride and bicarbonate ion channel found in many human cells. Its unique biochemical characteristics and role as a member of the adenosine triphosphate (ATP)-binding cassette transporters superfamily are pivotal for the transport of several substrates across cellular membranes. CFTR is known to interact, physically and functionally, with several other cellular proteins. Hence, its properties are essential for moving various substances across cell membranes and ensuring correct cell functioning. Genetic mutations or environmental factors may disrupt CFTR's function resulting in different possible phenotypes due to gene variations that affect not only CFTR's function, localization, and processing within cells, but also those of its interactors. This has been reported as an underlying cause of various diseases, including cystic fibrosis. The severe clinical implications of cystic fibrosis have driven intense research into the role of CFTR in lung function but its significance to fertility, particularly in men, has been comparatively understudied. However, ongoing and more recent research into CFTR and its interacting proteins in the testis or specific testicular cells is beginning to shed light on this field. Herein, we provide a comprehensive and up-to-date overview of the CFTR, its interactome, and its crucial role in male reproduction, highlighting recent discoveries and advancements in understanding the molecular mechanisms involved. The comprehension of these complex interactions may pave the way for potential therapeutic approaches to improve fertility of men suffering from alterations in the function of CFTR.

Recent Advances in Nanomaterials for Modulation of Stem Cell Differentiation and Its Therapeutic Applications.

Challenges in directed differentiation and survival limit the clinical use of stem cells despite their promising therapeutic potential in regenerative medicine. Nanotechnology has emerged as a powerful tool to address these challenges and enable precise control over stem cell fate. In particular, nanomaterials can mimic an extracellular matrix and provide specific cues to guide stem cell differentiation and proliferation in the field of nanotechnology. For instance, recent studies have demonstrated that nanostructured surfaces and scaffolds can enhance stem cell lineage commitment modulated by intracellular regulation and external stimulation, such as reactive oxygen species (ROS) scavenging, autophagy, or electrical stimulation. Furthermore, nanoframework-based and upconversion nanoparticles can be used to deliver bioactive molecules, growth factors, and genetic materials to facilitate stem cell differentiation and tissue regeneration. The increasing use of nanostructures in stem cell research has led to the development of new therapeutic approaches. Therefore, this review provides an overview of recent advances in nanomaterials for modulating stem cell differentiation, including metal-, carbon-, and peptide-based strategies. In addition, we highlight the potential of these nano-enabled technologies for clinical applications of stem cell therapy by focusing on improving the differentiation efficiency and therapeutics. We believe that this review will inspire researchers to intensify their efforts and deepen their understanding, thereby accelerating the development of stem cell differentiation modulation, therapeutic applications in the pharmaceutical industry, and stem cell therapeutics.

Alpha T-catenin: a crucial tumor suppressor in cancer pathogenesis.

Alpha T-catenin has recently been identified as a crucial tumor suppressor in various cancer types, with roles that go beyond just providing structural support in adherens junctions. This review brings together recent findings on alpha T-catenin's important involvement in key signaling pathways related to cancer progression. We present strong evidence of its regulatory role in Wnt signaling, a pathway often disrupted in colorectal cancer, and explain how it inhibits cell proliferation and tumor growth. We also discuss the significant downregulation of alpha T-catenin in colorectal cancers and its potential as a prognostic marker. Moreover, this review looks at how increasing alpha T-catenin levels can reduce tumor growth and spread, suggesting new therapeutic strategies. Additionally, we reveal alpha T-catenin's unexpected impact on NF-κB signaling in basal E-cadherin-negative breast cancer, expanding its importance across different cancer types. By bringing these findings together, we provide a thorough understanding of alpha T-catenin's tumor-suppressing actions, setting the stage for new targeted therapies and diagnostic tools in cancer treatment.

A case of endoscopic submucosal dissection of esophageal acantholytic Paget's disease with discontinuously spreading and unclear neoplastic extension.

BACKGROUND: Paget's disease (PD) is a carcinoma, in which irregular atypical cells with abundant cytoplasm proliferate mainly within the epithelium and is classified into PD occurring in the breast and extramammary Paget's disease (EMPD) occurring outside the breast. Essentially, extramammary PD is reported as a tumor for which it is difficult for surgeons to properly determine the line of resection. CASE PRESENTATION: An 83-year-old male was admitted to our hospital because of roughness of the esophageal epithelium during the follow-up examination for a gastric ulcer. A preoperative biopsy revealed squamous cell carcinoma; therefore, endoscopic submucosal dissection (ESD) was performed. CONCLUSIONS: The characteristic feature in this patient was the distribution of tumor cells and, accordingly, the difficulty in identifying the neoplastic distribution. In this patient, the odd distribution and growth pattern of the tumor cells made it difficult for the operator to identify the distribution of the lesion preoperatively.

Dysfunctional intestinal microvascular endothelial cells: Insights and therapeutic implications in gastrointestinal inflammation.

The intestinal microvascular endothelium plays a crucial role in orchestrating host responses to inflammation within the gastrointestinal tract. This review delves into the unique aspects of intestinal microvascular endothelial cells, distinct from those of larger vessels, in mediating leukocyte recruitment, maintaining barrier integrity, and regulating angiogenesis during inflammation. Specifically, their role in the pathogenesis of inflammatory bowel diseases, where dysregulated endothelial functions contribute to the disease progression, is reviewed. Furthermore, this review discusses the isolation technique for these cells and commonly used adhesion molecules for in vitro and in vivo experiments. In addition, we reviewed the development and therapeutic implications of a biologic agent targeting the interaction between α4ß7 integrin on T lymphocytes and mucosal addressin cellular adhesion molecule-1 on gut endothelium. Notably, vedolizumab, a humanized monoclonal antibody against α4ß7 integrin, has shown promising outcomes in inflammatory bowel diseases and other gastrointestinal inflammatory conditions, including chronic pouchitis, immune checkpoint inhibitor-induced colitis, and acute cellular rejection post-intestinal transplantation.

Cellular adhesion molecules in drug-naïve and previously medicated patients with schizophrenia-spectrum disorders.

BACKGROUND: Endothelial inflammation may be involved in the pathogenesis of schizophrenia, and cellular adhesion molecules (CAMs) on endothelial cells may facilitate leukocyte binding and transendothelial migration of cells and inflammatory factors. The aim of the present study was to assess levels of soluble cellular adhesion molecules, including intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, mucosal addressin cell adhesion molecule (MADCAM), junctional adhesion molecule (JAM-A) and neural cadherin (N-CAD) in patients with schizophrenia compared to healthy controls. METHODS: The study population consists of 138 patients with schizophrenia-spectrum disorder, of whom 54 were drug-naïve, compared to 317 general population controls. The potential confounders age, gender, smoking and body mass index (BMI) were adjusted for in linear regression models. RESULTS: The total patient group showed significantly higher levels of ICAM-1 (p < 0.001) and VCAM-1 (p < 0.001) compared to controls. Previously medicated patients showed higher ICAM-1 levels compared to drug-naïve patients (p = 0.042) and controls (p < 0.001), and elevated VCAM-1 levels compared to controls (p < 0.001). Drug-naive patients had elevated levels of VCAM-1 (p = 0.031) compared to controls. CONCLUSIONS: In our study, patients with schizophrenia - including the drug-naïve - have higher levels of soluble CAMs compared to healthy controls. These findings suggest activation of the endothelial system as in inflammation.

Associations of Circulating Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 With Long-Term Cardiac Function.

BACKGROUND: Although VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) have been associated with incident heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF), the associations of VCAM-1 and ICAM-1 with sensitive measures of cardiac structure/function are unclear. The objective of this study is to evaluate associations between VCAM-1, ICAM-1, and measures of cardiac structure and function as potential pathways through which cellular adhesion molecules promote HFpEF and AF risk. METHODS AND RESULTS: In MESA (Multi-Ethnic Study of Atherosclerosis), we evaluated the associations of circulating VCAM-1 and ICAM-1 at examination 2 (2002-2004) with measures of cardiac structure/function on cardiac magnetic resonance imaging at examination 5 (2010-2011) after multivariable adjustment. Mediation analysis of left atrial (LA) strain on the association between VCAM-1 or ICAM-1 and AF or HFpEF was also performed. Overall, 2304 individuals (63±10 years; 47% men) with VCAM-1 or ICAM-1, cardiac magnetic resonance imaging, and covariate data were included in analysis. Higher VCAM-1 and ICAM-1 were associated with lower LA peak longitudinal strain and worse global circumferential left ventricular strain but were not associated with left ventricular myocardial scar or interstitial fibrosis. Lower LA peak longitudinal strain mediated 8% (95% CI, 2-30) of the relationship between VCAM-1 and HFpEF and 9% (95% CI, 2-21) of the relationship between VCAM-1 and AF. CONCLUSIONS: Higher VCAM-1 and ICAM-1 were associated with lower LA function and left ventricular systolic function but were not associated with myocardial scar or interstitial fibrosis. VCAM-1 and ICAM-1 may promote HFpEF and AF risk through impaired LA reservoir function.

Spatial proteomics of ER tubules reveals CLMN, an ER-actin tether at focal adhesions that promotes cell migration.

The endoplasmic reticulum (ER) is structurally and functionally diverse, yet how its functions are organized within morphological subdomains is incompletely understood. Utilizing TurboID-based proximity labeling and CRISPR knock-in technologies, here we map the proteomic landscape of the human ER and nuclear envelope. Spatial proteomics reveals enrichments of proteins into ER tubules, sheets, and nuclear envelope. We uncover an ER-enriched actin-binding protein, Calmin (CLMN), and define it as an ER-actin tether that localizes to focal adhesions adjacent to ER tubules. CLMN depletion perturbs focal adhesion disassembly, actin dynamics, and cell movement. Mechanistically, CLMN-depleted cells also exhibit defects in calcium signaling near ER-actin interfaces, suggesting CLMN promotes calcium signaling near adhesions to facilitate their disassembly. Collectively, we map the sub-organelle proteome landscape of the ER, identify CLMN as an ER-actin tether, and describe a non-canonical mechanism by which ER tubules engage actin to regulate cell migration.

Metal-Induced Energy Transfer (MIET) Imaging of Cell Surface Engineering with Multivalent DNA Nanobrushes.

The spacing between cells has a significant impact on cell-cell interactions, which are critical to the fate and function of both individual cells and multicellular organisms. However, accurately measuring the distance between cell membranes and the variations between different membranes has proven to be a challenging task. In this study, we employ metal-induced energy transfer (MIET) imaging/spectroscopy to determine and track the intermembrane distance and variations with nanometer precision. We have developed a DNA-based molecular adhesive called the DNA nanobrush, which serves as a cellular adhesive for connecting the plasma membranes of different cells. By manipulating the number of base pairs within the DNA nanobrush, we can modify various aspects of membrane-membrane interactions such as adhesive directionality, distance, and forces. We demonstrate that such nanometer-level changes can be detected with MIET imaging/spectroscopy. Moreover, we successfully employed MIET to measure distance variations between a cellular plasma membrane and a model membrane. This experiment not only showcases the effectiveness of MIET as a powerful tool for accurately quantifying membrane-membrane interactions but also validates the potential of DNA nanobrushes as cellular adhesives. This innovative method holds significant implications for advancing the study of multicellular interactions.

The effect of augmenting suture material with magnesium and platelet-rich plasma on the in vitro adhesion and proliferation potential of subacromial bursa-derived progenitor cells.

Background: Connective tissue subacromial bursa-derived progenitor cells (SBDCs) have been suggested as a potent biologic augment to promote healing of the repaired rotator cuff tendon. Maximizing the amount of retained progenitor cells at the tendon repair site is essential for ensuring an optimal healing environment, warranting a search for proadhesive and proliferative adjuvants. The purpose was to evaluate the effect of magnesium (Mg), platelet-rich plasma (PRP), and a combination of both adjuvants on the in vitro cellular adhesion and proliferation potential of SBDCs on suture material commonly used in rotator cuff surgery. Methods: SBDCs were isolated from subacromial bursa samples harvested during rotator cuff repair and cultured in growth media. Commercially available collagen-coated nonabsorbable flat-braided suture was cut into 1-inch pieces, placed into 48-well culture dishes, and sterilized under ultraviolet light. Either a one-time dose of 5 mM sterile Mg, 0.2 mL of PRP, or a combination of both adjuvants was added, while a group without treatment served as a negative control. Cellular proliferation and adhesion assays on suture material were performed for each treatment condition. Results: Augmenting the suture with Mg resulted in a significantly increased cellular adhesion (total number of attached cells) of SBDCs compared to PRP alone (31,527 ± 19,884 vs. 13,619 ± 8808; P < .001), no treatment (31,527 ± 19,884 vs. 21,643 ± 8194; P = .016), and combination of both adjuvants (31,527 ± 19,884 vs. 17,121 ± 11,935; P < .001). Further, augmentation with Mg achieved a significant increase in cellular proliferation (absorbance) of SBDCs on suture material when compared to the PRP (0.516 ± 0.207 vs. 0.424 ± 0.131; P = .001) and no treatment (0.516 ± 0.207 vs. 0.383 ± 0.094; P < .001) group. The combination of Mg and PRP showed a significantly higher proliferation potential compared to PRP alone (0.512 ± 0.194 vs. 0.424 ± 0.131; P = .001) and no treatment (0.512 ± 0.194 vs. 0.383 ± 0.094; P < .001). There were no significant differences in the remaining intergroup comparisons (P > .05, respectively). Conclusion: Augmenting suture material with Mg resulted in a significantly increased cellular adhesion of SBDCs compared to untreated suture material, as well as augmentation with PRP alone or a combination of both adjuvants. Further, Mg with or without PRP augmentation achieved a significant increase in the cellular proliferation of SBDCs on suture material compared to untreated sutures and augmentation with PRP alone. Application of Mg may be a clinically feasible approach to optimizing the use of SBDCs as a biological augment in rotator cuff repair, while combined augmentation with PRP may harness the full potential for optimized tissue recovery due to the high concentration of PRP-derived growth factors.

Construction and Evaluation of Alginate Dialdehyde Grafted RGD Derivatives/Polyvinyl Alcohol/Cellulose Nanocrystals IPN Composite Hydrogels.

To enhance the mechanical strength and cell adhesion of alginate hydrogel, making it satisfy the requirements of an ideal tissue engineering scaffold, the grafting of Arg-Gly-Asp (RGD) polypeptide sequence onto the alginate molecular chain was conducted by oxidation of sodium periodate and subsequent reduction amination of 2-methylpyridine borane complex (2-PBC) to synthesize alginate dialdehyde grafted RGD derivatives (ADA-RGD) with good cellular affinity. The interpenetrating network (IPN) composite hydrogels of alginate/polyvinyl alcohol/cellulose nanocrystals (ALG/PVA/CNCs) were fabricated through a physical mixture of ion cross-linking of sodium alginate (SA) with hydroxyapatite/D-glucono-δ-lactone (HAP/GDL), and physical cross-linking of polyvinyl alcohol (PVA) by a freezing/thawing method, using cellulose nanocrystals (CNCs) as the reinforcement agent. The effects of the addition of CNCs and different contents of PVA on the morphology, thermal stability, mechanical properties, swelling, biodegradability, and cell compatibility of the IPN composite hydrogels were investigated, and the effect of RGD grafting on the biological properties of the IPN composite hydrogels was also studied. The resultant IPN ALG/PVA/CNCs composite hydrogels exhibited good pore structure and regular 3D morphology, whose pore size and porosity could be regulated by adjusting PVA content and the addition of CNCs. By increasing the PVA content, the number of physical cross-linking points in PVA increased, resulting in greater stress support for the IPN composite hydrogels of ALG/PVA/CNCs and consequently improving their mechanical characteristics. The creation of the IPN ALG/PVA/CNCs composite hydrogels' physical cross-linking network through intramolecular or intermolecular hydrogen bonding led to improved thermal resistance and reduced swelling and biodegradation rate. Conversely, the ADA-RGD/PVA/CNCs IPN composite hydrogels exhibited a quicker degradation rate, attributed to the elimination of ADA-RGD by alkali. The results of the in vitro cytocompatibility showed that ALG/0.5PVA/0.3%CNCs and ADA-RGD/PVA/0.3%CNCs composite hydrogels showed better proliferative activity in comparison with other composite hydrogels, while ALG/PVA/0.3%CNCs and ADA-RGD/PVA/0.3%CNCs composite hydrogels displayed obvious proliferation effects, indicating that PVA, CNCs, and ADA-RGD with good biocompatibility were conducive to cell proliferation and differentiation for the IPN composite hydrogels.

Association of Inflammatory and Oxidative Status Markers with Metabolic Syndrome and Its Components in 40-to-45-Year-Old Females: A Cross-Sectional Study.

Oxidative stress and sterile inflammation play roles in the induction and maintenance of metabolic syndrome (MetS). This study cohort included 170 females aged 40 to 45 years who were categorized according to the presentation of MetS components (e.g., central obesity, insulin resistance, atherogenic dyslipidemia, and elevated systolic blood pressure) as controls not presenting a single component (n = 43), those with pre-MetS displaying one to two components (n = 70), and females manifesting MetS, e.g., ≥3 components (n = 53). We analyzed the trends of seventeen oxidative and nine inflammatory status markers across three clinical categories. A multivariate regression of selected oxidative status and inflammatory markers on the components of MetS was performed. Markers of oxidative damage (malondialdehyde and advanced-glycation-end-products-associated fluorescence of plasma) were similar across the groups. Healthy controls displayed lower uricemia and higher bilirubinemia than females with MetS; and lower leukocyte counts, concentrations of C-reactive protein, interleukine-6, and higher levels of carotenoids/lipids and soluble receptors for advanced glycation end-products than those with pre-MetS and MetS. In multivariate regression models, levels of C-reactive protein, uric acid, and interleukine-6 were consistently associated with MetS components, although the impacts of single markers differed. Our data suggest that a proinflammatory imbalance precedes the manifestation of MetS, while an imbalance of oxidative status accompanies overt MetS. Further studies are needed to elucidate whether determining markers beyond traditional ones could help improve the prognosis of subjects at an early stage of MetS.

Mesenchymal stromal cell-associated migrasomes: a new source of chemoattractant for cells of hematopoietic origin.

BACKGROUND: Multipotent mesenchymal stromal cells (MSCs) are precursors of various cell types. Through soluble factors, direct cell-cell interactions and other intercellular communication mechanisms such as extracellular vesicles and tunneling nanotubes, MSCs support tissue homeostasis. In the bone marrow microenvironment, they promote hematopoiesis. The interaction between MSCs and cancer cells enhances the cancer and metastatic potential. Here, we have demonstrated that plastic-adherent MSCs isolated from human bone marrow generate migrasomes, a newly discovered organelle playing a role in intercellular communication. RESULTS: Migrasomes are forming a network with retraction fibers behind the migrating MSCs or surrounding them after membrane retraction. The MSC markers, CD44, CD73, CD90, CD105 and CD166 are present on the migrasome network, the latter being specific to migrasomes. Some migrasomes harbor the late endosomal GTPase Rab7 and exosomal marker CD63 indicating the presence of multivesicular bodies. Stromal cell-derived factor 1 (SDF-1) was detected in migrasomes, suggesting that they play a chemoattractant role. Co-cultures with KG-1a leukemic cells or primary CD34+ hematopoietic progenitors revealed that MSC-associated migrasomes attracted them, a process intercepted by the addition of AMD3100, a specific CXCR4 receptor inhibitor, or recombinant SDF-1. An antibody directed against CD166 reduced the association of hematopoietic cells and MSC-associated migrasomes. In contrast to primary CD34+ progenitors, leukemic cells can take up migrasomes. CONCLUSION: Overall, we described a novel mechanism used by MSCs to communicate with cells of hematopoietic origin and further studies are needed to decipher all biological aspects of migrasomes in the healthy and transformed bone marrow microenvironment. Video Abstract.

Advances in understanding the molecular structure of retinoschisin while questions remain of biological function.

Retinoschisin (RS1) is a secreted protein that is essential for maintaining integrity of the retina. Numerous mutations in RS1 cause X-linked retinoschisis (XLRS), a progressive degeneration of the retina that leads to vision loss in young males. A key manifestation of XLRS is the formation of cavities (cysts) in the retina and separation of the layers (schisis), disrupting synaptic transmission. There are currently no approved treatments for patients with XLRS. Strategies using adeno-associated viral (AAV) vectors to deliver functional copies of RS1 as a form of gene augmentation therapy, are under clinical evaluation. To improve therapeutic strategies for treating XLRS, it is critical to better understand the secretion of RS1 and its molecular function. Immunofluorescence and immunoelectron microscopy show that RS1 is located on the surfaces of the photoreceptor inner segments and bipolar cells. Sequence homology indicates a discoidin domain fold, similar to many other proteins with demonstrated adhesion functions. Recent structural studies revealed the tertiary structure of RS1 as two back-to-back octameric rings, each cross-linked by disulfides. The observation of higher order structures in vitro suggests the formation of an adhesive matrix spanning the distance between cells (∼100 nm). Several studies indicated that RS1 readily binds to other proteins such as the sodium-potassium ATPase (NaK-ATPase) and extracellular matrix proteins. Alternatively, RS1 may influence fluid regulation via interaction with membrane proteins such as the NaK-ATPase, largely inferred from the use of carbonic anhydrase inhibitors to shrink the typical intra-retinal cysts in XLRS. We discuss these models in light of RS1 structure and address the difficulty in understanding the function of RS1.

Regulation, Maintenance, and Remodeling of High Endothelial Venules in Homeostasis, Inflammation, and Cancer.

High endothelial venules (HEVs), high walled cuboidal blood vessels, through their expression of adhesion molecules and chemokines, allow the entrance of lymphoid cells into primary, secondary, and tertiary lymphoid structures (aka tertiary lymphoid organs). HEV heterogeneity exists between various lymphoid organs in their expression of peripheral node addressin (PNAd) and mucosal vascular addressin adhesion molecule 1(MAdCAM-1). Transcriptomic analyses reveal extensive heterogeneity, plasticity, and regulation of HEV gene expression in ontogeny, acute inflammation, and chronic inflammation within and between lymphoid organs. Rules regulating HEV development are flexible in inflammation. HEVs in tumor tertiary lymphoid structures are diagnostic of favorable clinical outcome and response to Immunotherapy, including immune check point blockade. Immunotherapy induces HEVs and provides an entrance for naïve, central memory, and effector cells and a niche for stem like precursor cells. Understanding HEV regulation will permit their exploitation as routes for drug delivery to autoimmune lesions, rejecting organs, and tumors.

Prophylactic Treatment with Hydrogen Sulphide Can Prevent Renal Ischemia-Reperfusion Injury in L-NAME Induced Hypertensive Rats with Cisplatin-Induced Acute Renal Failure.

(Background and Objectives): Renal ischemia perfusion injury is one of the major issues in kidney transplant. The aim of the study was to investigate the hypothesis that prophylactic treatment-with a hydrogen sulphide donor to an acute renal failure case of hypertensive rats-can minimize the ischemia reperfusion injury of the kidney which is beneficial for kidney transplant. To check this hypothesis, the present study was designed to investigate the effect of chronic administration of a hydrogen sulphide (H2S) donor and sodium hydrosulfide (NaHS) on nuclear factor kappa B (NF-kB) and inter cellular adhesion molecule-1 (ICAM-1) concentration in non-renal failure (NRF) and acute renal failure (ARF) rats in the ischemia-reperfusion injury (IRI) model of the kidney in both normotensive WKY and hypertensive rats (L-nitro arginine methyl ester (L-NAME-induced); (Materials and Methods): A total number of 48 Sprague-Dawley rats were recruited into eight groups each consisting of six animals. Each of these eight groups was used to measure systemic and renal parameters, H2S, antioxidant parameters in plasma, plasma concentration of NF-kB and ICAM-1 and renal cortical blood pressure. ARF was induced by single intraperitoneal (i.p.) cisplatin injection (5 mg/kg). Hypertension was induced by oral administration of L-NAME in drinking water for four weeks at 40 mg/kg/day. NaHS was administered (i.p) at 56 µmol/kg for five weeks while dL-propargylglycine (PAG), a H2S generation inhibitor, was administered as a single intra-peritoneal injection (50 mg/kg). An acute surgical experiment was performed for the induction of renal ischemia for 30 min by renal artery clamping followed by reperfusion for three hours; (Results): Chronic administration of NaHS attenuated the severity of ARF in both normotensive and hypertensive animals (L-NAME) along with lowering the blood pressure in hypertensive groups. NaHS improved the oxidative stress parameters such as total superoxide dismutase (T-SOD), glutathione (GSH) and reduced the malondialdehyde (MDA) concentration along with reduction of NF-kB and ICAM-1 following renal IRI; Conclusions: These findings demonstrate that H2S not only reduced the severity of cisplatin induced ARF but also reduced the severity of renal IRI by upregulating antioxidants along with decreased concentrations of NF-kB and ICAM-1 in normotensive and L-NAME induced hypertensive rats.

Fabrication of Conductive Tissue Engineering Nanocomposite Films Based on Chitosan and Surfactant-Stabilized Graphene Dispersions.

Chitosan (CS)/graphene nanocomposite films with tunable biomechanics, electroconductivity and biocompatibility using polyvinylpyrrolidone (PVP) and Pluronic F108 (Plu) as emulsion stabilizers for the purpose of conductive tissue engineering were successfully obtained. In order to obtain a composite solution, aqueous dispersions of multilayered graphene stabilized with Plu/PVP were supplied with CS at a ratio of CS to stabilizers of 2:1, respectively. Electroconductive films were obtained by the solution casting method. The electrical conductivity, mechanical properties and in vitro and in vivo biocompatibility of the resulting films were assessed in relation to the graphene concentration and stabilizer type and they were close to that of smooth muscle tissue. According to the results of the in vitro cytotoxicity analysis, the films did not release soluble cytotoxic components into the cell culture medium. The high adhesion of murine fibroblasts to the films indicated the absence of contact cytotoxicity. In subcutaneous implantation in Wistar rats, we found that stabilizers reduced the brittleness of the chitosan films and the inflammatory response.

A novel porous granular scaffold for the promotion of trabecular bone repair by time-dependent alteration of morphology.

Granular scaffolds have been extensively used in the clinic to repair irregular maxillofacial defects. There remain some challenges for the repair of trabecular structures in cancellous bone due to the reticular lamella-like morphology. In this study, we fabricated a novel granular scaffold by rational design of components with different degradation rates so that the morphology of the novel scaffold can evolve to match the growth period of bone cells. Here, polycaprolactone (PCL) was used to fabricate porous microspheres as a skeleton with slow degradation. The macropores were filled with quick degraded gelatin to form complete microspheres. Asynchronous degradation of the two components altered the morphology of the evolutive scaffold from compact to porous, gradually exposing the ridge-like skeletons. This scaffold reversed the decline of cellular adhesion to simple porous skeletons during the initial adhesion. Furthermore, the cells were able to grow into the pores and adhere onto the skeletons with an elongated cellular morphology, facilitating osteogenic differentiation. This novel scaffold was experimentally proven to promote the regeneration of alveolar bone along with a good percentage of bone volume and the formation of trabecular structures. We believe this morphology-evolved scaffold is highly promising for regenerative applications in the clinic.

Influence of Elasticity of Hydrogel Nanoparticles on Their Tumor Delivery.

Polymeric nanocarriers have a broad range of clinical applications in recent years, but an inefficient delivery of polymeric nanocarriers to target tissues has always been a challenge. These results show that tuning the elasticity of hydrogel nanoparticles (HNPs) improves their delivery efficiency to tumors. Herein, a microfluidic system is constructed to evaluate cellular uptake of HNPs of different elasticity under flow conditions. It is found that soft HNPs are more efficiently taken up by cells than hard HNPs under flow conditions, owing to the greater adhesion between soft HNPs and cells. Furthermore, in vivo imaging reveals that soft HNPs have a more efficient tumor delivery than hard HNPs, and the greater targeting potential of soft HNPs is associated with both prolonged blood circulation and a high extent of cellular adhesion.

Influence of Polydatin on the Tumor Microenvironment In Vitro: Studies with a Colon Cancer Cell Model.

The tumor microenvironment of colon carcinoma, the site at which tumor cells and the host immune system interact, is influenced by signals from tumor cells, immunocompetent cells, and bacterial components, including LPS. A large amount of LPS is available in the colon, and this could promote inflammation and metastasis by enhancing tumor cell adhesion to the endothelium. Polydatin (PD), the 3-ß-D-glucoside of trans-resveratrol, is a polyphenol with anti-cancer, anti-inflammatory, and immunoregulatory effects. This study was designed to explore whether PD is able to produce antiproliferative effects on three colon cancer lines, to reduce the expression of adhesion molecules that are upregulated by LPS on endothelial cells, and to decrease the proinflammatory cytokines released in culture supernatants. Actually, we investigated the effects of PD on tumor growth in a coculture model with human mononuclear cells (MNCs) that mimics, at least in part, an in vitro tumor microenvironment. The results showed that PD alone or in combination with MNC exerts antiproliferative and proapoptotic effects on cancer cells, inhibits the production of the immunosuppressive cytokine IL-10 and of the proinflammatory cytokines upregulated by LPS, and reduces E-selectin and VCAM-1 on endothelial cells. These data provide preclinical support to the hypothesis that PD could be of potential benefit as a therapeutic adjuvant in colon cancer treatment and prevention.