Functional Zwitterionic Polyurethanes: State-of-the-Art Review.

Recent advancements in bioengineering and medical devices have been greatly influenced and dominated by synthetic polymers, particularly polyurethanes (PUs). PUs offer customizable mechanical properties and long-term stability, but their inherent hydrophobic nature poses challenges in practically biological application processes, such as interface high friction, strong protein adsorption, and thrombosis. To address these issues, surface modifications of PUs for generating functionally hydrophilic layers have received widespread attention, but the durability of generated surface functionality is poor due to irreversible mechanical wear or biodegradation. As a result, numerous researchers have investigated bulk modification techniques to incorporate zwitterionic polymers or groups onto the main or side chains of PUs, thereby improving their hydrophilicity and biocompatibility. This comprehensive review presents an extensive overview of notable zwitterionic PUs (ZPUs), including those based on phosphorylcholine, sulfobetaine, and carboxybetaine. The review explores their wide range of biomedical applications, from blood-contacting devices to antibacterial coatings, fouling-resistant marine coatings, separation membranes, lubricated surfaces, and shape memory and self-healing materials. Lastly, the review summarizes the challenges and future prospects of ZPUs in biological applications.

Expression Regulation and Trafficking of Aquaporins.

Aquaporins (AQPs) mediate the bidirectional water flow driven by an osmotic gradient. Either gating or trafficking allows for rapid and specific AQP regulation in a tissue-dependent manner. The regulatory mechanisms of AQP2 are discussed mainly in this chapter, as the mechanisms controlling the regulation and trafficking of AQP2 have been very well studied. The targeting of AQP2 to the apical plasma membrane of collecting duct principal cells is mainly regulated by the action of arginine vasopressin (AVP) on the type 2 AVP receptor (V2R), which cause increased intracellular cAMP or elevated intracellular calcium levels. Activation of these intracellular signaling pathways results in vesicles bearing AQP2 transport, docking and fusion with the apical membrane, which increase density of AQP2 on the membrane. The removal of AQP2 from the membrane requires dynamic cytoskeletal remodeling. AQP2 is degraded through the ubiquitin proteasome pathway and lysosomal proteolysis pathway. Finally, we review updated findings in transcriptional and epigenetic regulation of AQP2.

GSK-3ß inhibitor TDZD-8 prevents reduction of aquaporin-1 expression via activating autophagy under renal ischemia reperfusion injury.

Renal ischemia/reperfusion (I/R) injury is a main cause of acute kidney injury (AKI). Aquaporin (AQP)-1 water channel in the kidney is critical for the maintenance of water homeostasis and the urinary concentrating ability. Increasing evidence supports an important role of autophagy in the pathogenesis of AKI induced by renal I/R. The purpose of the present study is to investigate whether activation of autophagy prevents downregulation of AQP1 protein induced by renal I/R and potential molecular mechanisms. Renal I/R induced consistently reduced protein expression of AQP1, 2, and 3, as well as sodium cotransporters Na+ -K+ -2Cl- cotransporter and α-Na,K-ATPase, which was associated with increased urine output and decreased creatinine clearance in rats. Renal I/R also suppressed autophagy and increased inflammatory responses in the kidney. 4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), the glycogen synthase kinase-3ß inhibitor, ameliorated renal injury under I/R, activated autophagy and markedly increased expression of AQPs and sodium transporters in the kidney, which was associated with improved urine output and creatinine clearance in rats. Hypoxia/reoxygenation (H/R) induced suppression of autophagy and downregulation of AQP1 in murine inner medullary collecting duct 3 (IMCD3) cells, which was fully prevented by TDZD-8 treatment. Inhibition of autophagy by 3-methyladenine or Atg5 gene knockdown attenuated recovery of AQP1 protein expression induced by TDZD-8 in IMCD3 cells with H/R. Interleukin-1 beta (IL-1ß) decreased the abundance of AQP1 protein in IMCD3 cells. H/R induced increases in protein expression of nod-like receptor pyrin domain-containing 3 and IL-1ß, which was reversed by TDZD-8. In conclusion, TDZD-8 treatment prevented downregulation of AQP1 expression under renal I/R injury, likely via activating autophagy and decreasing IL-1ß production.

Bioinspired Polysaccharide Derivative with Efficient and Stable Lubrication for Silicon-Based Devices.

It is becoming increasingly important to synthesize efficient biomacromolecule lubricants suitable for medical devices. Even though the development of biomimetic lubricants has made great progress, the current system suitable for hydrophobic silicone-based medical devices is highly limited. In this work, we synthesize one kind of novel polysaccharide-derived macromolecule lubricant of chitosan (CS) grafted polyethylene glycol (PEG) chains and catechol groups (CT) (CS-g-PEG-g-CT). CS-g-PEG-g-CT shows good adsorption ability by applying quantitative analysis of quartz crystal microbalance (QCM), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), and confocal fluorescence imaging technique, as well as the typical shear-thinning feature. CS-g-PEG-g-CT exhibits low and stable coefficients of friction (COFs) (0.01-0.02) on polydimethylsiloxane (PDMS) surfaces at a wide range of mass concentrations in diverse media including pure water, physiological saline, and PBS buffer solution and is even tolerant to various normal loads and sliding frequencies for complex pressurizing or shearing environments. Subsequently, systematic surface characterizations are used to verify the dynamic attachment ability of the CS-g-PEG-g-CT lubricant on the loading/shearing process. The lubrication mechanism of CS-g-PEG-g-CT can be attributed to the synergy of strong adsorption from catechol groups to form a uniform assembly layer, excellent hydration effect from PEG chains, and typical shear-thinning feature to dissipate viscous resistance. Surprisingly, CS-g-PEG-g-CT exhibits efficient lubricity on silicone-based commercial contact lenses and catheters. The current macromolecule lubricant demonstrates great real application potential in the fields of medical devices and disease treatments.

Statins attenuate cholesterol-induced ROS via inhibiting NOX2/NOX4 and mitochondrial pathway in collecting ducts of the kidney.

BACKGROUND: Statins therapy has been primarily recommended for the prevention of cardiovascular risk in patients with chronic kidney diseases. Statins has also been proved some benefits in lipid-induced kidney diseases. The current study aims to investigate the protection and underlying mechanisms of statins on renal tubular injuries induced by cholesterol overloaded. METHODS: We used tubular suspensions of inner medullary collecting duct (IMCD) cells from rat kidneys and mouse collecting duct cell line mpkCCD cells to investigate the effect of statins on reactive oxygen species (ROS) production induced by cholesterol. Protein and mRNA expression of NADPH oxidase 2 (NOX2) /NOX4 was examined by Western blot and RT-PCR in vitro studies and in rats with 5/6 nephrectomy and high-fat diet. Mitochondrial morphology and membrane potential was observed by Mito-tracker and JC-1. RESULTS: Statins treatment was associated with decreased NOX2 and NOX4 protein expression and mRNA levels in 5/6Nx rats with high-fat diet. Statins treatment markedly reduced the ROS production in IMCD suspensions and mpkCCD cells. Also, statins reduced NOX2 and NOX4 protein expression and mRNA levels in cholesterol overload mpkCCD cells and improved mitochondrial morphology and function. CONCLUSION: Statins prevented ROS production induced by cholesterol in the kidney, likely through inhibiting NOXs protein expression and improving mitochondrial function. Statins may be a therapeutic option in treating obesity-associated kidney diseases.

Successive Redox-Reaction-Triggered Interface Radical Polymerization for Growing Hydrogel Coatings on Diverse Substrates.

Growing lubricating hydrogel coatings in controllable manners on diverse material surfaces demonstrates promising applications. Here, a surface modification method is reported for in situ growing hydrogel coatings onto surfaces of diverse substrates in the absence of UV assistance. It is performed by decorating substrates with a universal mussel-inspired synthetic adhesive with catechol groups. Upon being immersed in reaction solution, these groups can assist substrate bonding and in situ capture and reduce Fe3+ into Fe2+ for decomposing S2 O8 2- into SO4 - ⋅ catalytically at the interface to initiate interface polymerization of monomers. As a result, hydrogel coatings with controllable thickness could be grown on surfaces of arbitrary substrates to change their surface characteristics regardless of materials size, category, geometry and transparency, implying considerable potential in surface engineering.

Genome-wide selection signatures detection in Shanghai Holstein cattle population identified genes related to adaption, health and reproduction traits.

BACKGROUND: Over several decades, a wide range of natural and artificial selection events in response to subtropical environments, intensive pasture and intensive feedlot systems have greatly changed the customary behaviour, appearance, and important economic traits of Shanghai Holstein cattle. In particular, the longevity of the Shanghai Holstein cattle population is generally short, approximately the 2nd to 3rd lactation. In this study, two complementary approaches, integrated haplotype score (iHS) and runs of homozygosity (ROH), were applied for the detection of selection signatures within the genome using genotyping by genome-reduced sequence data from 1092 cows. RESULTS: In total, 101 significant iHS genomic regions containing selection signatures encompassing a total of 256 candidate genes were detected. There were 27 significant |iHS| genomic regions with a mean |iHS| score > 2. The average number of ROH per individual was 42.15 ± 25.47, with an average size of 2.95 Mb. The length of 78 % of the detected ROH was within the range of 1-2 MB and 2-4 MB, and 99 % were shorter than 8 Mb. A total of 168 genes were detected in 18 ROH islands (top 1 %) across 16 autosomes, in which each SNP showed a percentage of occurrence > 30 %. There were 160 and 167 genes associated with the 52 candidate regions within health-related QTL intervals and 59 candidate regions within reproduction-related QTL intervals, respectively. Annotation of the regions harbouring clustered |iHS| signals and candidate regions for ROH revealed a panel of interesting candidate genes associated with adaptation and economic traits, such as IL22RA1, CALHM3, ITGA9, NDUFB3, RGS3, SOD2, SNRPA1, ST3GAL4, ALAD, EXOSC10, and MASP2. In a further step, a total of 1472 SNPs in 256 genes were matched with 352 cis-eQTLs in 21 tissues and 27 trans-eQTLs in 6 tissues. For SNPs located in candidate regions for ROH, a total of 108 cis-eQTLs in 13 tissues and 4 trans-eQTLs were found for 1092 SNPs. Eighty-one eGenes were significantly expressed in at least one tissue relevant to a trait (P value < 0.05) and matched the 256 genes detected by iHS. For the 168 significant genes detected by ROH, 47 gene-tissue pairs were significantly associated with at least one of the 37 traits. CONCLUSIONS: We provide a comprehensive overview of selection signatures in Shanghai Holstein cattle genomes by combining iHS and ROH. Our study provides a list of genes associated with immunity, reproduction and adaptation. For functional annotation, the cGTEx resource was used to interpret SNP-trait associations. The results may facilitate the identification of genes relevant to important economic traits and can help us better understand the biological processes and mechanisms affected by strong ongoing natural or artificial selection in livestock populations.

Activation of TGR5 restores AQP2 expression via the HIF pathway in renal ischemia-reperfusion injury.

Renal ischemia-reperfusion (I/R) injury is associated with markedly reduced protein expression of aquaporins (AQPs). Membrane G protein-coupled bile acid receptor-1 (TGR5) has shown protective roles in some kidney diseases. The purpose of the current study was to investigate whether activation of TGR5 prevented the decreased protein expression of AQPs in rodents with renal I/R injury and potential mechanisms. TGR5 agonist lithocholic acid (LCA) treatment reduced polyuria after renal I/R injury in rats. LCA prevented the decreased abundance of AQP2 protein and upregulated hypoxia-inducible factor (HIF)-1α protein expression, which were associated with decreased protein abundance of NF-κB p65 and IL-1ß. After renal I/R, mice with tgr5 gene deficiency exhibited further decreases in AQP2 and HIF-1α protein abundance and increases of IL-1ß and NF-κB p65 protein expression compared with wild-type mice. In primary cultured inner medullary collecting duct cells with hypoxia/reoxygenation, LCA induced markedly increased protein expression of AQP2 and HIF-1α, which were partially prevented by the PKA inhibitor H89. FG4592, a prolyl-4-hydroxylase domain-containing protein inhibitor, increased HIF-1α and AQP2 protein abundance in association with decreased NF-κB p65 protein expression in inner medullary collecting duct cells with hypoxia/reoxygenation. In conclusion, TGR5 stimulation by LCA prevented downregulation of renal AQPs in kidney with I/R injury, likely through activating HIF-1α signaling and suppressing inflammatory responses.NEW & NOTEWORTHY Stimulation of the membrane G protein-coupled bile acid receptor TGR5 by lithocholic acid (LCA) reduced polyuria in rats with renal ischemia-reperfusion (I/R) injury. LCA increased abundance of aquaporin-2 (AQP2) protein and upregulated hypoxia-inducible factor (HIF)-1α protein expression in association with decreased NF-κB p65 and IL-1ß. After I/R, mice with tgr5 gene deficiency exhibited more severe decreases in AQP2 and HIF-1α protein abundance and inflammatory responses. TGR5 activation exhibits a protective role in acute renal injury induced by I/R.

Bile Acid G Protein-Coupled Membrane Receptor TGR5 Modulates Aquaporin 2-Mediated Water Homeostasis.

BACKGROUND: The bile acid-activated receptors, including the membrane G protein-coupled receptor TGR5 and nuclear farnesoid X receptor (FXR), have roles in kidney diseases. In this study, we investigated the role of TGR5 in renal water handling and the underlying molecular mechanisms. METHODS: We used tubule suspensions of inner medullary collecting duct (IMCD) cells from rat kidneys to investigate the effect of TGR5 signaling on aquaporin-2 (AQP2) expression, and examined the in vivo effects of TGR5 in mice with lithium-induced nephrogenic diabetes insipidus (NDI) and Tgr5 knockout (Tgr5-/-) mice. RESULTS: Activation of TGR5 by lithocholic acid (LCA), an endogenous TGR5 ligand, or INT-777, a synthetic TGR5-specific agonist, induced AQP2 expression and intracellular trafficking in rat IMCD cells via a cAMP-protein kinase A signaling pathway. In mice with NDI, dietary supplementation with LCA markedly decreased urine output and increased urine osmolality, which was associated with significantly upregulated AQP2 expression in the kidney inner medulla. Supplementation with endogenous FXR agonist had no effect. In primary IMCD suspensions from lithium-treated rats, treatment with INT-767 (FXR and TGR5 dual agonist) or INT-777, but not INT-747 (FXR agonist), increased AQP2 expression. Tgr5-/- mice exhibited an attenuated ability to concentrate urine in response to dehydration, which was associated with decreased AQP2 expression in the kidney inner medulla. In lithium-treated Tgr5-/- mice, LCA treatment failed to prevent reduction of AQP2 expression. CONCLUSIONS: TGR5 stimulation increases renal AQP2 expression and improves impaired urinary concentration in lithium-induced NDI. TGR5 is thus involved in regulating water metabolism in the kidney.

Combination of Chymostatin and Aliskiren attenuates ER stress induced by lipid overload in kidney tubular cells.

BACKGROUND: Lipotoxicity plays an important role in the pathogenesis of kidney injury. Our previous study demonstrated that activation of local renin-angiotensin system (RAS) was involved in saturated free fatty acids palmitic acid (PA)-induced tubular cell injuries. The current study aims to investigate whether suppression of RAS by combination of direct renin inhibitor aliskiren and noncanonical RAS pathway chymase inhibitor chymostatin attenuates PA or cholesterol induced-endoplasmic reticulum stress (ER stress) and apopotosis in cultured human proximal tubular HK2 cells. METHODS: HK2 cells were treated with saturated fatty acid PA (0.6 mM) for 24 h or cholesterol (10 µg/ml) for 6d with or without chymostatin and/or aliskiren. Expressions of the ER stress associated proteins and apoptosis markers were detected by western blotting. The mRNA levels of RAS components were measured by real-time qPCR. RESULTS: Combination treatment of chymostatin and aliskiren markedly suppressed PA or cholesterol-induced ER stress, as reflected by increased BiP, IRE1α, phosphorylated-eIF2α and ATF4 as well as proapoptotic transcription factor CHOP. The ratio of Bax/Bcl-2 and cleaved caspase-3, two markers of apoptosis were upregulated by PA or cholesterol treatment. PA treatment was also associated with increased levels of angiotensinogen and angiotensin type 1 receptor (AT1R) mRNA expression. Combination treatment of chymostatin and aliskiren markedly suppressed PA or cholesterol-induced ER stress and apoptosis. The protective effect of two inhibitors was also observed in primary cultured cortical tubular cells treated with PA. In contrast, chymostatin and/or aliskiren failed to prevent ER stress induced by tunicamycin. CONCLUSIONS: These results suggested that combination treatment of chymostatin and aliskiren attenuates lipid-induced renal tubular cell injury, likely through suppressing activation of intracellular RAS.

Mechanosensing by Piezo1 and its implications in the kidney.

Piezo1 is an essential mechanosensitive transduction ion channel in mammals. Its unique structure makes it capable of converting mechanical cues into electrical and biological signals, modulating biological and (patho)physiological processes in a wide variety of cells. There is increasing evidence demonstrating that the piezo1 channel plays a vital role in renal physiology and disease conditions. This review summarizes the current evidence on the structure and properties of Piezo1, gating modulation, and pharmacological characteristics, with special focus on the distribution and (patho)physiological significance of Piezo1 in the kidney, which may provide insights into potential treatment targets for renal diseases involving this ion channel.

Novel biomimetic macromolecules system for highly efficient lubrication, ROS scavenging and osteoarthritis treatment.

The early stages of osteoarthritis (OA) in the joints are typically characterized by two key factors: the dysfunction of articular cartilage lubrication and inflammation resulting from the excessive production of reactive oxygen species (ROS). Synthetic injectable macromolecular materials present great potential for preventing the progression of early OA. In this study, to mimic the excellent lubricity of brush-like aggregates found in natural synovial fluid, we develop a novel macromolecular biolubricant (CS-PS-DA) by integrating adhesion and hydration groups onto backbone of natural biomacromolecules. CS-PS-DA exhibits a strong affinity for cartilage surfaces, enabling the formation of a stable lubrication layer at the sliding interface of degraded cartilages to restore joint lubrication performance. In vitro results from ROS scavenging and anti-inflammatory experiments indicate the great advantage of CS-PS-DA to decrease the levels of proinflammatory cytokines by inhibiting ROS overproduction. Finally, in vivo rats OA model demonstrates that intra-cavitary injection of CS-PS-DA could effectively resist cartilage wear and mitigated inflammation in the joints. This novel biolubricant provides a new and timely strategy for the treatment of OA.

Mechanically Robust Lubricating Hydrogels Beyond the Natural Cartilage as Compliant Artificial Joint Coating.

Natural cartilage exhibits superior lubricity as well as an ultra-long service lifetime, which is related to its surface hydration, load-bearing, and deformation recovery feature. Until now, it is of great challenge to develop reliable cartilage lubricating materials or coatings with persistent robustness. Inspired by the unique biochemical structure and mechanics of natural cartilage, the study reports a novel cartilage-hydrogel composed of top composite lubrication layer and bottom mechanical load-bearing layer, by covalently manufacturing thick polyelectrolyte brush phase through sub-surface of tough hydrogel matrix with multi-level crystallization phase. Due to multiple network dissipation mechanisms of matrix, this hydrogel can achieve a high compression modulus of 11.8 MPa, a reversible creep recovery (creep strain: ≈2%), along with excellent anti-swelling feature in physiological medium (v/v0 < 5%). Using low-viscosity PBS as lubricant, this hydrogel demonstrates persistent lubricity (average COF: ≈0.027) under a high contact pressure of 2.06 MPa with encountering 100k reciprocating sliding cycles, negligible wear and a deformation recovery of collapse pit in testing area. The extraordinary lubrication performance of this hydrogel is comparable to but beyond the natural animal cartilage, and can be used as compliant coating for implantable articular material of UHMWPE to present, offering more robust lubricity than current commercial system.

Surface functionalization of polyurethanes: A critical review.

Synthetic polymers, particularly polyurethanes (PUs), have revolutionized bioengineering and biomedical devices due to their customizable mechanical properties and long-term stability. However, the inherent hydrophobic nature of PU surfaces arises common issues such as high friction, strong protein adsorption, and thrombosis, especially in the physiological environment of blood contact. To overcome these issues, researchers have explored various modification techniques to improve the surface biofunctionality of PUs. In this review, we have systematically summarized several typical surface modification methods including surface plasma modification, surface oxidation-induced grafting polymerization, isocyanate-based chemistry coupling, UV-induced surface grafting polymerization, adhesives-assisted attachment strategy, small molecules-bridge grafting, solvent evaporation technique, and hydrogen bonding interaction. Correspondingly, the advantages, limitations, and future prospects of these surface modification methods were discussed. This review provides an important guidance or tool for developing surface functionalized PUs in the fields of bioengineering and medical devices.

Biomimetic chitosan-derived bifunctional lubricant with superior antibacterial and hydration lubrication performances.

The lubrication deficiency in joints is a major cause of osteoarthritis. One of the most commonly used treatment means is to inject artificial lubricants, but there is a potential risk of infection during the injection process. Therefore, developing artificial lubricants with dual functions of friction-reduction and antibacterial is urgent. In this work, a novel polysaccharide-derived lubricant with simultaneous anti-bacteria and water-lubrication properties, called CS-MPC-N, is developed by grafting 2­methacryloyloxylethyl phosphorylcholine (MPC) and nisin peptide onto backbone of chitosan (CS). Compared to the control CS, CS-MPC-N exhibits good lubrication and friction-reduction properties because of its excellent water solubility. Especially, CS-MPC-N shows low friction coefficient (0.03 âˆ¼ 0.05) at the sliding interfaces of artificial joints materials or even natural articular cartilages. Moreover, CS-MPC-N can effectively inhibit the proliferation of Staphylococcus aureu, exhibiting excellent antibacterial effect. This kind of novel polysaccharide-derived lubricant is expected to be used in treating infectious arthritis.

Electrospun fibrous membrane reinforced hydrogels with preferable mechanical and tribological performance as cartilage substitutes.

Hydrogels have attracted much attention as cartilage substitutes due to their human tissue-like characteristics. However, developing cartilage substitutes require the combination of high mechanical strength and low friction. Despite great success in tough hydrogels, this combination was hardly realized. Inspired by the natural cartilage, electrospun fibrous membrane reinforced hydrogels with superior mechanical properties and low friction coefficient were designed using electrospinning, freeze-thawing, and annealing techniques. An ordered fibrous membrane was first constructed by electrospinning, in which the tensile strength and modulus have been improved successfully. Then the PVA/PAA/GO hydrogel was modified layer-by-layer by the multilayer ordered electrospun membrane of PVA/PAA/GO. The ordered fibrous membrane significantly enhanced the mechanical strength and friction properties in a manner that mimicked the collagen fibrils in the cartilage. When the number of the membranes was 4, the mechanical properties of the fibrous membrane reinforced hydrogel is maximized, which can be compared to natural cartilage, which can achieve a tensile strength of 13.7 ± 1.5 MPa, tensile modulus of 27.5 ± 3.2 MPa, compressive strength of 12.32 ± 1.35 MPa, compressive modulus of 20.35 ± 2.50 MPa. The ordered fibrous membrane endows the hydrogel with a higher tearing energy of 39.16 ± 4.05 KJ m-2, which is the 5 times that of pure hydrogel (7.74 ± 0.86 KJ m-2). In addition, the friction coefficient of the fibrous membrane reinforced hydrogel is as low as 0.039, 2 times smaller than that of the hydrogel without addition of the fibrous membrane. Therefore, such hydrogels had excellent mechanical properties and tribological properties, which could be widely used in tissue engineering such as in cartilage replacement.

Gut-derived ß-amyloid: Likely a centerpiece of the gut-brain axis contributing to Alzheimer's pathogenesis.

Peripheral ß-amyloid (Aß), including those contained in the gut, may contribute to the formation of Aß plaques in the brain, and gut microbiota appears to exert an impact on Alzheimer's disease (AD) via the gut-brain axis, although detailed mechanisms are not clearly defined. The current study focused on uncovering the potential interactions among gut-derived Aß in aging, gut microbiota, and AD pathogenesis. To achieve this goal, the expression levels of Aß and several key proteins involved in Aß metabolism were initially assessed in mouse gut, with key results confirmed in human tissue. The results demonstrated that a high level of Aß was detected throughout the gut in both mice and human, and gut Aß42 increased with age in wild type and mutant amyloid precursor protein/presenilin 1 (APP/PS1) mice. Next, the gut microbiome of mice was characterized by 16S rRNA sequencing, and we found the gut microbiome altered significantly in aged APP/PS1 mice and fecal microbiota transplantation (FMT) of aged APP/PS1 mice increased gut BACE1 and Aß42 levels. Intra-intestinal injection of isotope or fluorescence labeled Aß combined with vagotomy was also performed to investigate the transmission of Aß from gut to brain. The data showed that, in aged mice, the gut Aß42 was transported to the brain mainly via blood rather than the vagal nerve. Furthermore, FMT of APP/PS1 mice induced neuroinflammation, a phenotype that mimics early AD pathology. Taken together, this study suggests that the gut is likely a critical source of Aß in the brain, and gut microbiota can further upregulate gut Aß production, thereby potentially contributing to AD pathogenesis.

Injectable carboxymethyl chitosan/nanosphere-based hydrogel with dynamic crosslinking network for efficient lubrication and sustained drug release.

The typical symptoms of arthritis are inflammation and lubrication deficiency in joints, which increase wear of articular cartilage along with pain of patients. In the present study, one kind of novel macromolecular/microsphere-based injectable hydrogels (CMC-ODex NPs) with dual functionalities of drug release and lubrication, was fabricated via dynamic Schiff base crosslinking network between carboxymethyl chitosan (CMC) and oxidation dextran nanoparticles (ODex NPs). The CMC-ODex NPs hydrogels exhibited typical viscosity-thinning phenomenon at wide range of shear rates and obvious gel-sol transition feature at specific strain. As a result, CMC-ODex NPs hydrogels presented low friction coefficient at the sliding interface of bovine articular cartilages, resulting from the boundary lubrication of hydrogel and the rolling friction effect of ODex NPs. Furthermore, the anti-inflammatory drug (dexamethasone, DXM) encapsulated in ODex NPs exhibited sustainable drug release behavior during the dynamic shearing process, which making CMC-ODex NPs hydrogels possessed good and stable anti-inflammatory effect. CMC-ODex NPs hydrogels was prepared without utilizing any toxic agents, thus demonstrated excellent cytocompatibility. Our experimental results reveal the CMC-ODex NPs hydrogels is promising to be used as functional lubricant for inhibiting the development of arthritis.

Biomimetic chitosan nanoparticles with simultaneous water lubricant and anti-inflammatory.

Rheumatoid arthritis (RA) is a chronic inflammatory immune and lubrication dysfunction disease that causes great damage to the joints. Herein, inspired by the unique biochemistry structure and excellent hydration of chondroitin sulfate (CHI) existing in joint system, one kind of novel polysaccharide nanoparticle lubricant, that is chitosan nanoparticles (CS NPs) grafting CHI (CS-CHI), is synthesized by one-step surface chemistry reaction. CHI with negative charges can form hydration layers on the surface of CS NPs, thus improving the lubricity of nanoparticles. Simultaneously, CS-CHI NPs have effective loading and sustained drug release ability for anti-inflammatory drug diclofenac sodium (DS), along with good biocompatibility. Finally, based on a collagen-induced rat RA model, in vitro animals experimental results indicate that the as-synthesized CS-CHI@DS NPs has obvious inhibitory effects on inflammatory factors and can effectively prevent the damaged cartilage from further destruction.

Autophagy is involved in degradation of AQP1 in response to an acute decrement in tonicity.

Renal medullary aquaporin-1 (AQP1) plays an important role in the urinary concentration. This study aimed to investigate the regulation of AQP1 by low osmotic stress and a potential role of autophagy. Low osmotic stress induced a dramatically decreased AQP1 protein expression in murine inner medullary collecting duct 3 (mIMCD3) cells, which was associated with a marked activation of autophagy. Inhibition of autophagy by 3-methyladenine (3-MA), chloroquine, or knockdown of autophagy-related protein 5 (ATG5) prevented the decrease in AQP1 protein abundance. Rapamycin-induced autophagy was associated with a decreased AQP1 protein expression and an enhanced interaction between AQP1 and ATG5 in mIMCD3 cells under low osmotic stress. In kidney inner medulla of mice given a 3% NaCl solution, activation of autophagy was associated with decreased AQP1 protein expression, which was prevented by 3-MA. In conclusion, low osmotic stress induced autophagy which contributed to the decreased AQP1 protein expression in the renal medulla.